11p Microdeletion including WT1 but not PAX6, presenting with cataract, mental retardation, genital abnormalities and seizures: a case report
© Almind et al; licensee BioMed Central Ltd. 2009
Received: 08 February 2009
Accepted: 17 February 2009
Published: 17 February 2009
WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities and mental retardation) and Potocki-Shaffer syndrome are rare contiguous gene deletion syndromes caused by deletions of the 11p14-p12 chromosome region.
We present a patient with mental retardation, unilateral cataract, bilateral ptosis, genital abnormalities, seizures and a dysmorphic face. Cytogenetic analysis showed a deletion on 11p that was further characterized using FISH and MLPA analyses. The deletion (11p13-p12) located in the area between the deletions associated with the WAGR and Potocki-Shaffer syndromes had a maximum size of 8.5 Mb and encompasses 44 genes. Deletion of WT1 explains the genital abnormalities observed. As PAX6 was intact the cataract observed cannot be explained by a deletion of this gene. Seizures have been described in Potocki-Shaffer syndrome while mental retardation has been described in both WAGR and Potocki-Shaffer syndrome. Characterization of this patient contributes further to elucidate the function of the genes in the 11p14-p12 chromosome region.
The clinical association of Wilms' tumor, aniridia, genitourinary abnormalities and mental retardation (WAGR) is a contiguous gene deletion syndrome caused by a deletion on the short arm of chromosome 11. The syndrome is caused by haploinsufficiency for the PAX6 gene (causing aniridia) and the WT1 gene (predisposing Wilms' tumor, genital abnormalities and nephropathies). Aniridia is clinically required for the diagnosis . Most WAGR patients are mentally retarded to some extent, and obesity has occasionally been noted, however the genetic causes for these traits have not been elucidated [2–5]. Recently Xu et al hypothesised that the SLC1A2, PRRG4 and BDNF genes might contribute to the abnormal mental development .
Potocki-Shaffer syndrome (PSS) is another gene deletion syndrome caused by a deletion on chromosome 11, but more proximal (11p11.2) than the WAGR deletion. The syndrome is characterized by foramina parietalia permanga, multiple exostoses and in some cases craniofacial dysostosis and mental retardation. Haploinsufficiency for EXT2 and ALX4 explains exostoses and parietal foramina respectively [7–9].
We present here a patient with an 8.5 Mb deletion on chromosome 11 located in the area between the WAGR and PSS deletions (11p13-p12).
A 15-year-old boy was referred to us for cytogenetic studies. He was the first child of unrelated parents. Pregnancy and delivery at term (41 weeks of gestation, birth weight 3220 g and length 50 cm) were normal and uneventful.
In the neonatal period cryptorchidism and hypospadias were noted. Upon surgery the testes were found atrophic as well. Nine years old he began to have seizures that were treated medically. After medication a weight gain from the 75 centile to just beneath the 97 centile (weight-for-height ratio) was noted.
The patient presented in this work shows mental retardation, unilateral cataract, bilateral ptosis, genital abnormalities, seizures and a dysmorphic face. It is uncertain whether the obesity observed is a side effect of the treatment for seizures or if it is part of the syndrome. The deletion breakpoints were mapped using FISH and MLPA analyses. The distal breakpoint was mapped between the PAX6 and RCN1 genes, while the proximal breakpoint was mapped to lie either within or proximal to the LRRC4C gene (Figure 2). The deletion encompasses a total of 44 genes or open reading frames, including the WT1 gene, which explains the genital abnormalities observed. As PAX6 is left intact the cataract observed cannot be explained by a deletion of this gene. One explanation may be that regulatory elements of PAX6 is deleted as such elements have been demonstrated . Regulatory elements, located 5' to the Pax6 gene important for lens induction have been identified in mouse [12, 13]. These upstream elements were not involved in the deletion in the patient described here, and it is purely speculative that others could exist. Another explanation is that the cataract is due to other genes involved in the deletion or causes unrelated to the deletion.
McGaughran et al. reported a case with a cytogenetic visible 11p deletion (del11(p11.2p14) . This patient exhibited features of both WAGR as well as PSS; developmental delay but no seizures. Bremond-Gignac et al described a further case with 11p deletion encompassing EXT2, ALX4, WT1 and PAX6 genes showing features of both WAGR and PSS . In addition, the patient showed obesity. Recently Xu et al. reported 31 WAGR cases and identified the genes deleted in each case using oligonucleotide array-CGH . Three of these cases had seizures. One patient had an intact PAX6 gene, however, ophthalmologic findings of the patient were not described since the scope of the paper was the mental retardation and autism observed in WAGR patients. Xu et al hypothesizes that SLC1A2 and BDNF contributes to the autism and mental retardation . In the patient presented here the SLC1A2 gene was deleted however the BDNF gene was intact.
Seizures have been described in PSS while mental retardation has been described in both WAGR and PSS. There are no obvious candidate genes for these symptoms, but our patient may help to further delineate phenotype-genotype relations in the area.
Written informed consent was obtained from the parents of the patient for publication with any accompanying images.
Wilms' tumor, Aniridia, Genitourinary abnormalities and mental Retardation
Fluorescence In Situ Hybridization
Multiplex Ligation Dependent Probe Amplification
Comparative Genomic Hybridization
We wish to thank Winni Pedersen, Kennedy Center, Glostrup, Denmark for technical assistance and the family for their contribution to this study.
- Fischbach BV, Trout KL, Lewis J, Luis CA, Sika M: WAGR syndrome: a clinical review of 54 cases. Pediatrics 2005, 116: 984–988. 10.1542/peds.2004-0467PubMedView ArticleGoogle Scholar
- Tiberio G, Digilio MC, Giannotti A: Obesity and WAGR syndrome. Clin Dysmorphol 2000, 9: 63–64. 10.1097/00019605-200009010-00014PubMedView ArticleGoogle Scholar
- Amor DJ: Morbid obesity and hyperphagia in the WAGR syndrome. Clin Dysmorphol 2002, 11: 73–74. 10.1097/00019605-200201000-00016PubMedView ArticleGoogle Scholar
- Lennon PA, Scott DA, Lonsdorf D, Wargowski DS, Kirkpatrick S, Patel A, Cheung SW: WAGR(O?) syndrome and congenital ptosis caused by an unbalanced t(11;15)(p13;p11.2)dn demonstrating a 7 megabase deletion by FISH. Am J Med Genet A 2006, 140: 1214–1218.PubMedView ArticleGoogle Scholar
- Marlin S, Couet D, Lacombe D, Cessans C, Bonneau D: Obesity: a new feature of WAGR (del 11p) syndrome. Clin Dysmorphol 1994, 3: 255–257. 10.1097/00019605-199407000-00012PubMedView ArticleGoogle Scholar
- Xu S, Han JC, Morales A, Menzie CM, Williams K, Fan YS: Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism. Cytogenet Genome Res 2008, 122: 181–187. 10.1159/000172086PubMedView ArticleGoogle Scholar
- Shaffer LG, Hecht JT, Ledbetter DH, Greenberg F: Familial interstitial deletion 11(p11.12p12) associated with parietal foramina, brachymicrocephaly, and mental retardation. Am J Med Genet 1993, 45: 581–583. 10.1002/ajmg.1320450512PubMedView ArticleGoogle Scholar
- Potocki L, Shaffer LG: Interstitial deletion of 11(p11.2p12): a newly described contiguous gene deletion syndrome involving the gene for hereditary multiple exostoses (EXT2). Am J Med Genet 1996, 62: 319–325. Publisher Full Text 10.1002/(SICI)1096-8628(19960329)62:3<319::AID-AJMG22>3.0.CO;2-MPubMedView ArticleGoogle Scholar
- Bartsch O, Wuyts W, Van Hul W, Hecht JT, Meinecke P, Hogue D, Werner W, Zabel B, Hinkel GK, Powell CM, Shaffer LG, Willems PJ: Delineation of a contiguous gene syndrome with multiple exostoses, enlarged parietal foramina, craniofacial dysostosis, and mental retardation, caused by deletions in the short arm of chromosome 11. Am J Hum Genet 1996, 58: 734–742.PubMed CentralPubMedGoogle Scholar
- Fantes JA, Bickmore WA, Fletcher JM, Ballesta F, Hanson IM, van HV: Submicroscopic deletions at the WAGR locus, revealed by nonradioactive in situ hybridization. Am J Hum Genet 1992, 51: 1286–1294.PubMed CentralPubMedGoogle Scholar
- Kammandel B, Chowdhury K, Stoykova A, Aparicio S, Brenner S, Gruss P: Distinct cis-essential modules direct the time-space pattern of the Pax6 gene activity. Dev Biol 1999, 205: 79–97. 10.1006/dbio.1998.9128PubMedView ArticleGoogle Scholar
- Williams SC, Altmann CR, Chow RL, Hemmati-Brivanlou A, Lang RA: A highly conserved lens transcriptional control element from the Pax-6 gene. Mech Dev 1998, 73: 225–229. 10.1016/S0925-4773(98)00057-4PubMedView ArticleGoogle Scholar
- Dimanlig PV, Faber SC, Auerbach W, Makarenkova HP, Lang RA: The upstream ectoderm enhancer in Pax6 has an important role in lens induction. Development 2001, 128: 4415–4424.PubMedGoogle Scholar
- McGaughran JM, Ward HB, Evans DG: WAGR syndrome and multiple exostoses in a patient with del(11)(p11.2p14.2). J Med Genet 1995, 32: 823–824. 10.1136/jmg.32.10.823PubMed CentralPubMedView ArticleGoogle Scholar
- Bremond-Gignac D, Crolla JA, Copin H, Guichet A, Bonneau D, Taine L, Lacombe D, Baumann C, Benzacken B, Verloes A: Combination of WAGR and Potocki-Shaffer contiguous deletion syndromes in a patient with an 11p11.2-p14 deletion. Eur J Hum Genet 2005, 13: 409–413. 10.1038/sj.ejhg.5201358PubMedView ArticleGoogle Scholar
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