The extent of clinical expression in cases of segmental aneuploidy often varies depending on the size of the chromosomal region involved. Here we present clinical and cytogenetic findings in a 5-month old boy with a duplication of a chromosomal segment 4p16.1→4pter and a deletion of a chromosomal segment 8p23.1→8pter. His karyotype was determined by applying classical GTG banding and FISH method (WHCR region, centromere 4, centromere 8, telomere 8p) as 46,XY,der(8)t(4;8)(p16.1;p23.1).ish der(8)t(4;8)(D8S504-,WHCR+,D8Z2+)dn. Parents are not related and have normal karyotypes, indicating de novo origin. We have compared similarity of the clinical features in our proband to other patients carrying only a duplication of the distal part of 4p or a deletion of distal part of 8p or similar combination described in the literature

Feodora Stipoljev

Ivana Škrlec

Jasenka Wagner

Marija Heffer

Silvija Pušeljić

English

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Coll. Antropol. 38 (2014) 1: 319–323Case ReportDe Novo Case of a Partial Trisomy 4p anda Partial Monosomy 8pIvana [krlec1, Jasenka Wagner1, Silvija Pu{elji}2, Marija Heffer1 and Feodora Stipoljev1,31 »J. J. Strossmayer« University, School of Medicine, Department of Medical Biology, Cytogenetic laboratory, Osijek, Croatia2 »J. J. Strossmayer« University, University Hospital Centre Osijek, Pediatric Clinic, Osijek, Croatia3 University of Zagreb, »Sveti Duh« University Hospital, Department of Obstetrics and Gynecology, Cytogenetic laboratory,Zagreb, CroatiaA B S T R A C TThe extent of clinical expression in cases of segmental aneuploidy often varies depending on the size of the chromo-somal region involved. Here we present clinical and cytogenetic findings in a 5-month old boy with a duplication of achromosomal segment 4p16.1®4pter and a deletion of a chromosomal segment 8p23.1®8pter. His karyotype was deter-mined by applying classical GTG banding and FISH method (WHCR region, centromere 4, centromere 8, telomere 8p) as46,XY,der(8)t(4;8)(p16.1;p23.1).ish der(8)t(4;8)(D8S504-,WHCR+,D8Z2+)dn. Parents are not related and have normalkaryotypes, indicating de novo origin. We have compared similarity of the clinical features in our proband to other pa-tients carrying only a duplication of the distal part of 4p or a deletion of distal part of 8p or similar combination de-scribed in the literature.Key words: chromosome aberrations, clinical findings, partial trisomy 4p, partial monosomy 8p, phenotypic vari-ability, unbalanced translocation, fluorescence in situ hybridizationIntroductionExtent of clinical expression in segmental aneuploidyoften varies with the size of chromosomal region in-volved. The translocation between short arm of chromo-some 4 and short arm of chromosome 8, in either a bal-anced or an unbalanced form, has been reported severaltimes1,2. Most of unbalanced published cases conferred toderivate chromosome 4p implicating on presence of par-tial trisomy 8p and monosmy 4p, respectively. De novo 4pdeletions are reasonably assumed to be single chromo-some anomalies. Unbalanced de novo translocations in-volving the short arms of chromosomes 4 and 8 weredetected with an unexpectedly high frequency in Wolf--Hirschhorn syndrome (WHS) patients3,4. Patients withder(4) had WHS, whereas subjects with der(8) showed amilder spectrum of dysmorphic features1. Zollino et al.4observed that in WHS patients with a de novo unbal-anced translocation t(4;8) the breakpoint in 8p recurredalways in the same region within olfactory receptor genecluster. On the contrary, breakpoints in 4p occurred attwo different sites; at a distance of approximately 5 and14Mb from the telomere, thus implying a different ex-tent of the 4p deletion4. Phenotype of the unbalancedt(4;8) patients is variable and there is no specific clinicalpattern which allows identification of these patients3.The short stature and severe mental retardation of thosewith the WHS contrasted sharply with the mild to mod-erate mental retardation, less severe dysmorphic fea-tures and physical overgrowth of those with the 4pl6.3duplication2,5.We have compared similarity of the clinical featuresin our proband to other patients carrying a solely dupli-cation of the distal part of 4p or a deletion of distal part of8p, and similar combination of unbalanced form, de-scribed in the literature.Case ReportThe proband is a 5-month old boy referred for geneticevaluation because of dysmorphic features. He was deliv-ered at term by cesarean section after uneventful preg-nancy. At birth, length was 52 cm, weight 3,360 g, and319Received for publication January 10, 2014head circumference 35 cm. There was no family historyof malformations or mental retardation. He showed adistinctive facial dysmorphic features: narrow forehead,hirsutism, wide nasal bridge, anteverted nostrils, low setand malformed ears, small mandible and low hairline onthe neck. Heart defect was present in the form of atrio-ventricular septal defect. A bilateral inguinal hernia withundescended right testicle was present. There were uni-lateral vesicoureteral reflux, grade III and diastasis ofthe rectus abdominis muscles by 3 cm. Magnetic reso-nance imaging of the brain showed hypoplasia of the cor-pus callosum. He had clinodactyly and low inserted thirdtoe. However, there was no growth delay. This study wasapproved by the Ethics Committee of the UniversityHospital Centre Osijek and School of Medicine, J. J.Strossmayer University Osijek and the written informedconsent was obtained from the parents of the proband.Cytogenetic and FISH AnalysisCytogenetic examination of GTG banded metaphases(at resolution of 550 bands) obtained by standard meth-ods6, showed an unbalanced proband’s karyotype withextra chromosome material at the short arm of the chro-mosome 8 (Figure 1) using Olympus BX61 microscopeand Cytovision 3.93 software (Applied Imaging, Eng-land). FISH (fluorescence in situ hybridization) with spe-cific probes (Vysis/Abbott) for centromere of chromo-some 4 (D4Z2), locus specific probe for Wolf-HirschhornSyndrome region (WHCR, 4p16.3), centromere 8 (D8Z2)and subtelomere of chromosome 8p (D8S504) on meta-phases showed presence of two hybridization signals forprobe WHCR (4p16.3) at each of the 4p and one addi-tional signal at the p arm of the derivate chromosome 8(Figure 2). Subtelomere 8p probe signal is present in onlyone copy and is missing from the derivative chromosome8. Subsequent chromosomal analysis of the parents re-vealed normal karyotypes. The karyotype of proband isthen 46,XY,der(8)t(4;8)(p16.1;p23.1).ish der(8)t(4;8)(D8-S504-,WHCR+,D8Z2+)dn.Discussion and ConclusionWe described a proband with dysmorphic features andan unbalanced translocation resulting in both partialtrisomy for 4p16.1®pter and partial monosomy for 8p-23.1®pter, respectively. We have compared similarity ofthe clinical features in our proband to other patients car-rying a duplication of the distal part of 4p7,8 and patientscarrying a deletion of distal part of 8p9,10–12 as describedin the literature (Table 1).Individuals with deletion of 8p are reported to share adistinctive pattern of clinical features which include lowbirth weight, congenital heart disease, developmental de-lay and a characteristic behaviour profile with hyperac-tivity and impulsiveness9,10,13,14. Patients with terminaldeletion 8p frequently have heart defects, especiallyatrioventricular septal defect and this led to the sugges-tion that this chromosome region may harbour a gene(GATA4, OMIM 600576) important in heart develop-ment10,11,15. Studies with model vertebrate systems haveimplicated GATA4, transcription factor as a critical regu-lator of cardiac gene expression and development16. Itshould be noted that not all patients with proven dele-tion of 8p23.1 have cardiac anomalies. Possible explana-tions are that the patients without cardiac pathology arenot deleted for GATA4 or, compensatory increases inI. [krlec et al.: Partial Duplication 4p and Partial Deletion 8p, Coll. Antropol. 38 (2014) 1: 319–323320Fig. 1. Partial karyotypes of the GTG banded chromosomes andideograms of a proband showing de novo derived chromosome 8.Fig. 2. Proband FISH analysis (A) using centromere probes 4 and 8 (D8Z2) and locus specific probe LSI WHS-4p16.3 and (B) usingcentromere probe 8 (D8Z2) and subtelomere probe 8p: D8S504 (Vysis/Abbott).GATA5 or GATA6 may mitigate the effects of GATA4 de-letion, and haploinsufficiency for other cardiac transcrip-tion factor genes (e.g. TBX5, NKX2–5) causes congenitalheart disease16. Alternatively, inherited mutations inother genes or stochastic events may impact on the se-verity of heart disease in patients haploinsufficient forGATA417. Deletion 8p23.1 should be considered in thedifferential diagnosis of cases suspected to have velo-cardiofacial syndrome10,17. Intellectual disability is themost frequently reported developmental outcome. Theredoes seem to be a relation between the size of the deletedregion on chromosome 8 and the degree of intellectualdisability, with more distal terminal deletions being asso-ciated with higher functioning12.On the other hand, more than 75 cases of trisomy 4phave been reported thus far, most of them due to unbal-anced translocations7,8. Trisomy 4p has been shown tocause specific phenotype associated with characteristicfacial appearance, postnatal growth retardation and se-vere psychomotor retardation with or without seizures,microcephaly and various major and minor anomalies.The large variability of the phenotype in trisomy 4p syn-drome may be explained by the variation in length andthe breakpoint location of the duplicated segments on4p7.To the best of our knowledge, until today there havebeen only few reports of a combination of duplication4p16.1®4pter and deletion 8p23.1®8pter syndrome15,17.With exception of microcephaly, synophrys, hyperte-lorism, retrognathia, pointed chin, short neck and rockerbottom feet, our proband had most of the clinical fea-tures associated with dup 4p syndrome. These includedlow hairline, hirsutism, wide nasal bridge, low set ears,clinodactyly, atrial septal defect and cryptorchidism. Thevariation in severity of phenotype may be related to suchvariables as age, sex and different size of chromosomesegment involved in dup 4p syndrome, as well as the ter-minal loss of genetic material of the second chromosomeinvolved in such an unbalanced translocation7,8. Themost of the cases of trisomy 4p have been due to unbal-anced translocations. In half of the cases, an acrocentricchromosome was involved18. The involved breakpointsvary between the cases, with consequently variation inphenotypes.There are only few published cases with a derivatechromosome 8p and a partial trisomy 4p and monosomyI. [krlec et al.: Partial Duplication 4p and Partial Deletion 8p, Coll. Antropol. 38 (2014) 1: 319–323321TABLE 1LIST OF CLINICAL SYMPTOMS CHARACTERISTIC FOR PARTIAL TRISOMY 4p AND PARTIAL MONOSOMY 8pPartial trisomy 4p(Gerard-Blanluet 2004,Demirhan 2010,Mau 2000)Partial monosomy 8p(Brocker-Vriends 1986,Blennow 1990, Hutchinson1992, Gilmore 2001)Our caseder(8)t(4;8)(p16.1;p23.1)Case ofder(8)t(4;8)(p12;p23)Mau et al. (2000)CraniofacialanomaliesMicrocephaly, low hairline,hirsutism, low set andenlarged ears, bulbosenose, broad nasal bridge,long eyelashes, synophrys,hypertelorism,retrognathia,micrognathia, pointedchin, short neckMicrocephaly, craniofacialdysmorphism, high andnarrow forehead, smalleyes, strabismus,hypertelorism, epicanthalfolds, long philtrum, shortnose, small jaw, irregularlyimplanted teeth,retrognathia, thin upper lip,low set and malformedears, narrow external earcanal, short neck,nystagmusLow hairline, hirsutism,narrow forehead, widenasal bridge, antevertednostrils, low set andmalformed ears, small jawHirsutism, low hairline,synophrs, high archedeyebrows, short nose witha wide nasal bridge,anteverted nostrils, fullcheeks, long philtrum, thinlips, flat palate, widelyspaced teeth, low set earsSkeletalanomaliesPointed chin,arachnodactyly,clinodactyly, rocker-bottom feetClinodactyly, low insertedthumb, widely spacednipples, rocker bottomfeet, hypoplastic toenailsClinodactyly, widelyspaced nipples, thirdtoe low insertedSmall hands with proximalplacement of the tumbs,dystrophic nails, fifthfonger clinodactyly, widelyspaced nipplesCardiovascularanomaliesAtrial septal defect Atrioventricular septaldefect, ductus arteriosus,pulmonary valve stenosis,patent ductus arteriosus,isomerism of the atria,tetralogy of FallotsAtrial septal defect Mild hypertrophy of theheartUrogenital andrenal anomaliesShawl scrotum,cryptorchidismHypospadias, undescendedtestis, cryptorchidism,horsehoe kidneys,bilateral ureteric refluxVesicoureteral refluxgrade III right side,bilateral inguinal hernia,diastasis rectus abdominis3 cm, undescended righttesticule (high in scrotum)Small clitoris8p, respectively. Our proband and case of der(8)t(4;8)(p12;p23)2 have some phenotypic similarity, such as: hir-sutism, low hairline, a wide nasal bridge, anteverted nos-trils, low set ears, and widely spaced nipples. Maas el al.17reported two patients with duplication of 4pl6 and dele-tion of 8p23.1, however, no clinical features were givenfor these cases15,17. One patient with the karyotype 46,XX,der(8)t(4;8)(p15.32;p22), was reported at 3 months ofage to be developmentally and physically normal5. Ac-cording to the Unique database19 with 10 affected mem-bers, level of learning difficulty ranges from severe tomild form, with some of them showing obsessive or com-pulsive behaviour patterns. The degree of mental handi-cap varies from moderate to mild with no specific behav-ioural characteristics5. They tend to be tall, which can beexplained by the presence of third copy of FGFR3 geneon the 4p16.3. That could be also an explanation for alack of growth retardation in our case. Facial features in-clude a slight asymmetry, widely spaced eyes, a smallnose and a short neck19. An abnormal muscular tone andin some children foot position can be cause of delayedgross motor skill development in most of the patientswith this translocation. Development of fine motor skillsis also very often affected19. This type of unbalanced formcomprises generalized overgrowth with a duplication of4p16.3, and mild to moderate mental retardation.Giglio et al.1 found that t(4p;8p) may be the most fre-quent translocation after the t(11q;22q), which is themost common reciprocal translocation in humans1,16.Since it involves regions of very similar size and bandingpattern, it may be undetected by a routine cytogeneticanalysis. Possible molecular mechanism of translocation4p;8p formation is an ectopic meiotic recombination be-tween the olfactory receptor gene clusters located onchromosome 4p and 8p. Those clusters, on molecular le-vel, are organized like heterozygous submicroscopic inver-sion and can cause a chromosomal imbalance involvingthose two chromosomal regions. That kind of chromo-somal rearrangements implies that inversion heterozy-gotes may be at risk of having a child with a de novo chro-mosomal rearrangement1,15. It was recently demonstratedthat WHS-associated t(4p;8p) translocations frequentlyoccur within olfactory receptor gene clusters on both 4pand 8p, with the involvement of two distinct olfactory re-ceptor gene clusters in 4p at a distance of about 5 and14Mb from the telomere and of a unique olfactory recep-tor gene cluster in 8p4. Proband’s parents can be inver-sion heterozygotes on molecular level for an olfactory re-ceptor gene clusters on both chromosome 4p and 8p, andthat can be the cause of unbalanced rearrangement alsoin our proband.Further case studies with a detailed clinical and mo-lecular characterization will certainly contribute to amore precise description of the deletion 8p syndrome andwill pinpoint the candidate region on chromosome 4 re-sponsible for partial trisomy 4p.R E F E R E N C E S1. GIGLIO S, CALVARI V, GREGATO G, GIMELLI G, CAMANINI S,GIORDA R, RAGUSA A, GUERNERI S, SELICORNI A, STUMM M, TON-NIES H, VENTURA M, ZOLLINO M, NERI G, BARBER J, WIECZO-REK D, ROCCHI M, ZUFFARDI O, Am J Hum Genet, 71 (2002) 276. — 2.MAU UA, BACKSCH C, SCHAUDT H, TREFZ FK, KAISER P, Am J MedGenet, 91 (2000) 180. DOI: 10.1002/(SICI) 1096-8628(20000320)91:3<180::AID-AJMG4>3.0.CO;2-R. — 3. TONNIES H, STUMM M, NEU-MANN L, VOLLETH M, GRUMPELT U, MUSEBECK J, ANNUSS G,NEITZEL H, J Med Genet, 38 (2001) 21. DOI: 10.1136/jmg.38.6.e21. — 4.ZOLLINO M, LECCE R, SELICORNI A, MURDOLO M, MANCUSO I,MARANGI G, ZAMPINO G, GARAVELLI L, FERRARINI A, ROCCHI M,OPITZ JM, NERI G, Eur J Hum Genet, 12 (2004) 797. DOI: 10.1038/sj.ejhg.5201203. — 5. PARTINGTON MW, FAGAN K, SOUBJAKI V,TURNER G, J Med Genet, 34 (1997) 153 DOI: 10.1136/jmg.34.9.719. — 6.MOORHEAD PS, NOWELL PC, MELLMAN WJ, BATTIPS DM, HUN-GERFORD DA, Exp Cell Res, 20 (1960) 613. — 7. DEMIRHAN O, ÖZ-GÜNEN FT, TASTEMIR D, Balk J Med Genet, 13 (2010) 8. — 8. GE-RARD-BLANLUET M, ROMANA S, MUNIER C, LE LORCH M, KANA-FANI S, SINICO M, TOUBOUL C, LEVAILLANT JM, HADDAD B,LOPEZ N, LELONG F, BILLETTE DE VILLEMEUR T, VERLOES A,BORGHI E, Am J Med Genet, 130A (2004) 299. DOI: 10.1002/ajmg.a.30314). — 9. BROCKER-VRIENDS AHJT, MOOIJ PD, VAN BELL F,BEVERSTOCK GC, VAN DE KAMP JJP, J Med Genet, 23 (1986) 153. —10. REDDY KS, Prenat Diagn, 19 (1999) 868 DOI: 10.1002/(SICI)1097-0223(199909) 19:9<868::AID-PD641>3.0.CO;2-A. — 11. DEVRIENDTK, MATTHIJS G, VAN DAEL R, GEWILLIG M, EYSKENS B, HJAL-GRIM H, DOLMER B, MCGAUGHRAN J, BRONDUM-NIELSEN K,MARYNEN P, FRYNS JP, VERMEESCH JR, Am J Hum Genet, 64 (1999)1119. — 12. GILMORE L, CUSKELLY M, JOBLING A, SMITH S, DevMed Child Neurol, 43 (2001) 843. DOI: 10. 1111/j.1469-8749.2001.tb00174.x. — 13. BLENNOW E, BRONDUM-NIELSEN K, J Med Genet, 27(1990) 327. — 14. HUTCHINSON R, WILSON M, VOULLAIRE L, J MedGenet, 29 (1992) 407. — 15. GIGLIO S, GRAW SL, GIMELLI G, PIROLAB, VARONE P, VOULLAIRE L, LERZO F, ROSSI E, DELLAVECCHIA C,BONAGLIA MC, DIGILIO MC, GIANNOTTI A, MARINO B, CARROZ-ZO R, KORENBERG JR, DANESINO C, SUJANSKY E, DALLAPICCO-LA B, ZUFFARDI O, Circulation, 102 (2000) 432. DOI: 10.1161/?01.CIR.102.4.432. — 16. PEHLIVAN T, POBER BR, BRUECKNER M, GAR-RETT S, SLAUGH R, VAN RHEEDEN R, WILSON DB, WATSON MS,HING AV, Am J Med Genet, 83 (1999) 201. DOI: 10.1002/(SICI)1096-8628(19990319)83:3<201::AID-AJMG11>3.0.CO;2-V. — 17. MAAS NMC,VAN VOOREN S, HANNES F, VAN BUGGENHOUT G, MYSLIWIEC M,MOREAU, FAGAN K, MIDRO A, ENGIZ O, BALCI S, PARKER MJ,SZNAJER Y, DEVRIENDT K, FRYNS JP, VERMEESCH JR, Genet Coun-seling, 18 (2007) 357. — 18. BARTOCCI A, STRIANO P, MANCARDIMM, FICHERA M, CASTIGLIA L, GALESI O, MICHELUCCI R, ELIAM, Brain Dev, 30 (2008) 425. DOI: 10.1016/j.braindev.2007.11.004. — 19.UNIQUE, The rare chromosome disorder support group, accessed 08.06.2013. Available from: URL: http://www.rarechromo.org/information/Chro-mosome%20%208/4p%208p%20Translocation%20FTNW.pdf.I. [krlecJ.J. Strossmayer University, School of Medicine, Cytogenetic laboratory, J. Huttlera 4, 31 000 Osijek, Croatiae-mail: iskrlec@mefos.hrI. [krlec et al.: Partial Duplication 4p and Partial Deletion 8p, Coll. Antropol. 38 (2014) 1: 319–323322DE NOVO SLU^AJ DJELOMI^NE TRISOMIJE 4p I DJELOMI^NE MONOSOMIJE 8pS A @ E T A KFenotip pacijenata s djelomi~nom aneuploidijom ~esto ima varijabilnu klini~ku sliku ovisnu o veli~ini kromosomskogsegmenta uklju~enog u translokaciju. Prikazane su klini~ke citogeneti~ke osobitosti dje~aka starog pet mjeseci s du-plikacijom dijela kromosoma 4p16.1®4pter i s gubitkom dijela kromosoma 8p23.1®pter. Kariotip probanda odre|en jeprimjenom klasi~nog GTG pruganja kromosoma i kori{tenjem FISH proba (lokus specifi~na proba za WHCR regiju,centromera 4, centromera 8, telomera 8p): 46,XY,der(8)t(4;8)(p16.1;p23.1).ish der(8)t(4;8)(D8S504–,WHCR+,D8Z2+)dn.Roditelji nisu u srodstvu i utvr|en im je normalan kariogram. Usporedili smo sli~nost klini~kih osobitosti na{eg pa-cijenta s ostalim pacijentima opisanim u literaturi koji imaju samo duplikaciju distalnog dijela 4p ili deleciju distalnogdijela 8p, ili sli~nu kombinaciju nebalansiranog kariotipa.I. [krlec et al.: Partial Duplication 4p and Partial Deletion 8p, Coll. Antropol. 38 (2014) 1: 319–323323

De Novo Case of a Partial Trisomy 4p and a Partial Monosomy 8p

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