Silver Russell syndrome due to maternal uniparental disomy 7 and a familial reciprocal translocation t(7;13)

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1 Clin Genet 2012: 82: Printed in Singaore. All rights reserved Short Reort 2011 John Wiley & Sons A/S CLINICAL GENETICS doi: /j x Silver Russell syndroe due to aternal uniarental disoy and a failial recirocal translocation t(;13) Behnecke A, Hinderhofer K, Jauch A, Janssen JWG, Moog U. Silver Russell syndroe due to aternal uniarental disoy and a failial recirocal translocation t(;13). Clin Genet 2012: 82: John Wiley & Sons A/S, 2011 Silver Russell syndroe (SRS) is a genetically heterogeneous disorder characterized by intrauterine and ostnatal growth retardation, tyical facial features and a sectru of additional features including body and lib asyetry and clinodactyly. Maternal uniarental disoy for chroosoe (ud()at) was shown to occur in 5 10% of atients with SRS. Maternal UPD is clinically often associated with ild SRS. Parents of an affected child are given a negligible recurrence risk as all reorted cases with ud()at have been soradic so far. In general, chroosoal rearrangeents-like translocations increase the likelihood of uniarental disoy (UPD) for the chroosoes involved. However, SRS as the result of a ud()at in association with an inherited chroosoal translocation involving chroosoe has only been reorted once before. Here, we describe the second case of SRS with ud()at due to a failial recirocal translocation t(;13). This ehasizes the iortance of chroosoe analysis in SRS atients with ud()at to rule out chroosoal rearrangeents desite their rare occurrence as they are of great relevance for genetic counseling of SRS failies. Conflict of interest All authors declare that there is no actual or otential conflict of interest in relation to this article. A Behnecke, K Hinderhofer, A Jauch, JWG Janssen and U Moog Institute of Huan Genetics, Heidelberg University, Heidelberg, Gerany Key words: aternal uniarental disoy recirocal chroosoal translocation Silver Russell syndroe trisoy rescue Corresonding author: Anne Behnecke, Institute of Huan Genetics, Heidelberg University, I Neuenheier Feld 344a, Heidelberg, Gerany. Tel.: ; fax: ; e-ail: anne.behnecke@ed. uni-heidelberg.de Received 8 July 2011, revised and acceted for ublication 26 Seteber 2011 Silver Russell syndroe (SRS) is a syndroe of reand ostnatal growth retardation in cobination with tyical dysorhic features, including a triangular face with down-turned corners of the outh, icrognathia, relative acrocehaly and roinent forehead, asyetry or heihyolasia of the face, libs or trunk, clinodactyly V, develoental delay and other features (1). SRS is a clinically variable and genetically heterogeneous disorder with aternal uniarental disoy (ud()at) being found in 5 10% of atients with SRS (2, 3). The ter uniarental disoy (UPD) in general describes the inheritance of both hoologous chroosoes fro one arent, with no contribution of that chroosoe fro the other arent. U to this oint, ore than 60 cases with SRS due to ud()at have been ublished, and although the clinical henotye by itself does not allow differentiation of the various causes of SRS, ost SRS atients with ud()at show a rather ild henotye (3). A disturbed exression of irinted genes on chroosoe ost robably exlains the henotye of SRS in atients with ud()at, and current research is focussing on different genes and candidate regions on chroosoe (1, 4). Different echaniss can lead to UPD. Chroosoal rearrangeents such as chroosoal translocations which are associated with an increased risk of aneuloidy have been reorted very rarely in atients with UPD. In fact, there is only one reort of an SRS atient due to ud()at, so far, who also carries a 494

2 Silver Russell syndroe (a) I:1 I:2 (b) 3 1 other? II:1 II:2 II:3 II:4 II:5 3/3 atient III:1 III:2 III:3 III:4 III:5 III:6 4 2 father IV:1 IV:2 IV:3 IV:4 (c) DS51 DS513 DS628 DS669 DS65 DS50 DS51 DS513 DS50 DS628 DS669 DS65 IVS1BTA DS640 DS684 DS63 DS IVS1BTA DS640 DS684 DS63 DS244 Chr. DS51 DS513 DS50 DS628 DS669 DS65 IVS1BTA DS640 DS684 DS63 DS244 Fig. 1. (a) Pedigree of faily. Affected boy (IV:4) labeled by filled-in square and arrow, carrier other (III:4) arked by dot. Grandother of the roositus (II:3) was not available for chroosoal analysis and is labeled by question ark. (b) Molecular testing for uniarental disoy revealing aternal UPD, exelarily shown by arker. (c) Scheatic illustration of the results of olecular testing for UPD revealing aternal UPD in the boy with Silver Russell syndroe. All the arkers used are in accord with aternal uniarental disoy (UPD) of the whole chroosoe. Arrows indicate the chroosoe regions covered by inforative arkers (black) and those of assuingly aternal origin (gray). translocation (5). We here describe the second case of ud()at and a recirocal, non-robertsonian translocation and discuss the consequences of this chroosoal finding for genetic counseling of the faily. Clinical reort The boy was born as the first child of healthy non-consanguineous Geran arents following three rior iscarriages of the coule within the first triester (Fig. 1a). Aside fro one iscarriage in the third triester reorted by his aternal grandother, both the aternal and the aternal faily histories were unrearkable. The roositus was born at 34 weeks of gestation by elective cesarean due to severe intrauterine growth restriction. Birth length was 38 c ( 2.5 SD), birth weight was 1400 g ( 1.5 SD) and head circuference (OFC) was 28 c ( 1.8 SD). Due to initial anoea and bradycardia he needed onitoring during his first days of life, but the following cardiological and internal exaination did not reveal any organic diseases or anoalies. Fro very early on, he resented with severe feeding difficulties, interittent hyoglyceia and recurrent eesis. Insulin-like growth factor 1 level was below noral, and the ossibility of growth horone substitution theray in the future was discussed with the arents. In contrast to his arkedly delayed seech develoent, he started walking at the age of 15 onths and continuously iroved his otor skills. When seen at the age of 2 years, he was severely growth retarded with a body length of 5 c ( 3.96 SD), a body weight of.6 kg ( 3.99 SD) and an occiitofrontal circuference (OFC) of 49 c ( 0.55 SD). He resented with ild facial dysorhis including a triangular face, down-turned corners of the outh, thin lis, a roinent forehead and relative acrocehaly. Heihyolasia or clinodactyly was not observed. He resented with well-develoed (fine) otor skills but still soke only very few words. Materials and ethods Cytogenetics and olecular genetics High-resolution GTG-banding chroosoe analyses were erfored on etahase rearations of eriheral blood lyhocytes fro the atient and the arents using standard techniques. The chroosoes were 495

3 Behnecke et al. analyzed and the karyotye described according to the International Syste for Cytogenetic Noenclature (2009). Fluorescence in situ hybridization (FISH) exerients were erfored as described before (6) using secific robes for the subteloeric regions of chroosoes 13q (PAC-163C9) and q (PAC-3K23) together with artial ainting robes for the long ar of chroosoes (cq) and 13 (c13q), resectively. Molecular genetic analysis Genoic DNA was extracted fro whole blood by use of standard salt reciitation rotocols. Genotyes for chroosoe -secific icrosatellite arkers DS51 (22.2), DS513 (21.3), DS50 (21.1), (15.3), DS628 (14.3), (12.3), DS669 (q21.11), DS65 (q21.3), IVS1BTA (q31.2), DS640 (q33), DS684 (q34), DS63 (q36.2), and DS244 (q36.2) were obtained by olyerase chain reaction, followed by olyacrylaide gel electrohoresis on an ALF exress sequencer. Results Molecular testing revealed ud()at and thereby confired the clinically susected diagnosis of SRS (Fig. 1b,c). Hetero- as well as isodisoy were detected. Because of hoozygosity in the other, soe arkers (DS51, DS513, DS50 and DS65) did not allow differentiation between iso- and hetereodisoic aternal inheritance. Although a few arkers were not inforative, all arkers used were in accord with aternal UPD of the whole chroosoe (Fig. 1c). In the following, high-resolution GTG banding of the other s etahases revealed a balanced translocation t(;13)(q11.2;q14). Subsequently, the translocation was shown in her son with SRS as well (Fig. 2). FISH confired these results (data not shown). The aternal grandother of the roositus who reortedly had one iscarriage in the third triester was not available for chroosoe analysis. 13q14 der(13) 13 q11.2 der() 13 Fig. 2. Karyotye analysis of the boy with Silver Russell syndroe discloses recirocal non-robertsonian chroosoal translocation t(;13)(q11.2;q14). Breakoints arked by arrows in scheatic illustration of the chroosoes involved (Cydas software, 20). Chroosoal analysis of the other shows the sae result (not ictured). Discussion In the index atient SRS was susected due to his clinical henotye with growth retardation, delayed seech develoent, and ild facial dysorhis. Testing of ud()at was erfored and confired the clinical diagnosis. Further cytogenetic analyses were initiated because of three receding iscarriages and revealed that he is a carrier of the recirocal translocation t(;13)(q11.2;q14) inherited fro his other. This is only the second reort of a atient with ud()at in association with a recirocal non-robertsonian chroosoal translocation involving chroosoe. UPD has been described for nearly every chroosoe, but only soe of the show a different henotye due to irinting effects (). Although structural chroosoe abnoralities are exected to increase the likelihood of UPD for the chroosoes involved, the actual risk of UPD is difficult to estiate. Berend et al. (8) described an eiric risk of % of finding UPD in Robertsonian translocation carriers whereas cases of hoologous acrocentric rearrangeents see to harbor a high risk of 66%. Assuingly, the risk for another child with SRS in the resent faily is only ildly increased, the actual risk of UPD associated with non-robertsonian translocation carriers, however, is currently unknown. Theoretically, every chroosoe abnorality that increases the occurrence of non-disjunction also increases the risk for UPD of the chroosoes involved. However, and not taking Robertsonian translocations into account, there are only very few cases ublished. To our knowledge there are only six reorts of carriers of recirocal translocations having offsring with UPD. Five of these translocations did not involve chroosoe and either led to the henotyes of Prader-Willi or Angelan syndroe (9 13) or ud(16)at with intrauterine growth retardation and inor facial anoalies (13). The only other case of an SRS atient with ud()at and a failial recirocal translocation was a girl with a aternally inherited t(;16)(q21;q24) recirocal translocation who showed a clinical henotye of growth retardation and inor facial dysorhis leading to a clinical tentative diagnosis of SRS (5). Further testing revealed aternal heterodisoy of chroosoe. In general, different echaniss can lead to UPD and all result fro an initial non-disjunctional event: trisoy rescue (loss of a suernuerary chroosoe), onosoy rescue (dulication of an unique chroosoe) and gaete coleentation (fertilization of a disoic gaete by a nullisoic one) (14). In the resented case, the trisoy rescue hyothesis sees to be ost lausible as the echanis of foration can be exlained best by 3:1 (interchange trisoy) segregation in oogenesis followed by the loss of the aternal chroosoe after fertilization of the oocyte (Fig. 3). Midro et al. (15) studied a faily with recirocal translocation carriers of the sae chroosoes involved as in our case but with different breakoints t(;13)(q34;q13) and found a high rate of 3:1 496

4 Silver Russell syndroe trisoy rescue Silver-Russell Syndroe :1 (interchange trisoy) der() der(13) 13 zygote der() der(13)13 der(13)13 der() der(13) der() ud()at Fig. 3. Scheatic illustration of trisoy rescue hyothesis leading to ud()at and Silver Russell syndroe in the secific case of a recirocal chroosoal translocation t(;13)(q11.2;q14). segregants, which also goes in line with the trisoy rescue hyothesis. They calculated a high robability rate of about 30% for stillbirth/early newborn deaths and iscarriages ( 13%) and a low robability for viable children with an unbalanced karyotye. As corroborated by the ositive faily history, the risk for stillbirth and iscarriages ay even be higher in the resent case as a del(13)(q14 qter) is assued to be lethal in ost of the affected concetuses and has been found reeatedly in sontaneous abortions. Live-born children resented with a severe clinical henotye and ostly died erinatally. Patients with du(13)(q14 qter) have been reorted ore frequently (16). They usually resent with noral re- and ostnatal growth but severe to rofound ental retardation, ultile caillary heangioata of the head and neck region, and various other alforations. Early lethality is assued to be higher than 50%. Live-born children with deletions or dulications of q11.2 qter have not been described so far. This exlains the high rate of iscarriages associated with the karyotye found in the faily described. Taken together, the reorted findings illustrate that conventional karyotying should be erfored in SRS atients with ud()at to exclude underlying chroosoal rearrangeents which are of high iact on further genetic counseling of the faily. We therefore suggest to add this diagnostic ste to the algorith schee recently ublished by Eggerann et al. (1) whenever ud()at has been confired in an SRS atient. In fact, if there had not been three iscarriages in the faily history, karyotye analysis ight not have been initiated at all, and the translocation with its consequences for the faily would have been overlooked. Therefore, this case also recalls the iortance of conventional karyotying in the first line diagnostic aroach in general as it roves to be an indisensable ethod for the detection of chroosoal rearrangeents in atients with ultile congenital anoalies or ental retardation. Being unaware of the karyotye, the arents would have been given a negligible recurrence risk for another child with SRS as recurrence is generally very unlikely due to the colex echaniss of foration leading to UPD. Recurrence risk is even considered to be so low that invasive renatal diagnosis is norally not indicated. Instead, further investigation revealed that the constitutional karyotye of the other harbors an increased risk of gaetes with an unbalanced karyotye and consequently a high risk rate of iscarriages or children with severe alforations and ental retardation, resectively. On the one hand this case suorts the relevance/indication of UPD testing in regnancies of carriers of chroosoal aberrations with articiation of irinted regions (12), on the other hand it has to be ket in ind that the clinical course of SRS as well as other irinting disorders, e.g. Beckwith-Wiedeann syndroe, cannot be redicted when diagnosed renatally. In consequence, all these situations require careful genetic counseling of the failies. Acknowledgeents We thank the atients and their arents whose hel and articiation ade this work ossible. References 1. Eggerann T, Begeann M, Binder G, Sengler S. Silver-Russell syndroe: genetic basis and olecular genetic testing. Orhanet J Rare Dis 2010: 5: Bruce S, Hannula-Joui K, Puoskari M et al. Subicroscoic genoic alterations in Silver-Russell syndroe and Silver-Russell-like atients. J Med Genet 2010: 4: Kotzot D. Maternal uniarental disoy and Silver-Russell syndroe - clinical udate and coarison with other subgrous. Eur J Med Genet 2008: 51: Kagai M, Nagai T, Fukai M, Yaazawa K, Ogata T. Silver-Russell syndroe in a girl born after in vitro fertilization: artial hyerethylation at the differentially ethylated region of PEG1/MEST. J Assist Rerod Genet 200: 24: Duont JM, Cuisset L, Cartigny M et al. Failial recirocal translocation t(;16) associated with aternal uniarental disoy in a Silver-Russell atient. A J Med Genet 2002: 111: Creer T, Po S, Eerich P, Lichter P, Creer C. Raid etahase and interhase detection of radiation-induced chroosoe aberrations in huan lyhocytes by chroosoal suression in situ hybridization. Cytoetry 1990: 11: Kotzot D. Colex and segental uniarental disoy udated. J Med Genet 2008: 45:

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