Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC83410.15690/vramn834MOLECULAR MEDICINE AND GENETICS: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ ГЕНЕТИКИ И МОЛЕКУЛЯРНОЙ МЕДИЦИНЫGENETIC APPROACHES TO DIFFERENTIAL DIAGNOSIS OF HEREDITARY FORMS OF CONGENITAL ANIRIDIAДИФФЕРЕНЦИАЛЬНАЯ ДИАГНОСТИКА НАСЛЕДСТВЕННЫХ ФОРМ ВРОЖДЕННОЙ АНИРИДИИ С ПОЗИЦИЙ СОВРЕМЕННОЙ ГЕНЕТИКИhttps://orcid.org/0000-0002-6744-0567VasilyevaT. A.ВасильеваТатьяна Алексеевна
Russian Federation

Moscow

Научный сотрудник лаборатории генетической эпидемиологии ФГБНУ «МГНЦ».

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vasilyeva_debrie@mail.ruhttps://orcid.org/0000-0003-4213-4923VoskresenskayaA. A.ВоскресенскаяАнна Александровна
Russian Federation

Cheboksary

Врач-офтальмолог отделения амбулаторной хирургии и консервативных методов лечения Чебоксарского филиала.

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vsolaris@mail.ruhttps://orcid.org/0000-0003-4947-4314KhlebnikovaO. V.ХлебниковаОльга Вадимовна
Russian Federation

Moscow

Доктор медицинских наук, ведущий научный сотрудник научно-консультативного отдела.

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khlebnikova@med-gen.ruhttps://orcid.org/0000-0003-3637-3645PozdeyevaN. A.ПоздееваНадежда Александровна

Cheboksary

Доктор медицинских наук, заместитель директора по научной работе Чебоксарского филиала ФГАУ «МНТК «Микрохирургия глаза» им. акад. С.Н. Федорова» Минздрава России

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npozdeeva@mail.ruhttps://orcid.org/0000-0002-0972-5118MarakhonovA. V.МарахоновАндрей Владимирович
Russian Federation

Moscow, Dolgoprudny

Старший научный сотрудник лаборатории генетической эпидемиологии ФГБНУ «МГНЦ», старший научный сотрудник лаборатории функционального анализа генома МФТИ.

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marakhonov@generesearch.ruhttps://orcid.org/0000-0003-3586-3458ZinchenkoR. A.ЗинченкоРена Абульфазовна

Moscow

Доктор медицинских наук, профессор, заведующая лабораторией генетической эпидемиологии ФГБНУ «МГНЦ», профессор кафедры молекулярной и клеточной генетики МБФ ФГБОУ ВО «РНИМУ им. Н.И. Пирогова» МР.

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renazinchenko@mail.ruResearch Center for Medical GeneticsМедико-генетический научный центрS. Fyodorov Eye Microsurgery Federal State InstitutionМежотраслевой научно-технический комплекс «Микрохирургия глаза» имени академика С.Н. Фёдорова, Чебоксарский филиалMoscow Institute of Physics and Technology (State University)Московский физико-технический институт (государственный университет)Pirogov Russian National Research Medical UniversityРоссийский национальный исследовательский медицинский университет имени Н.И. Пирогова180920177242332412204201725072017Copyright ©; 2017, "Paediatrician" Publishers LLCCopyright ©; 2017, Издательство "Педиатръ"2017"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/834

Congenital aniridia (AN) is a hereditary autosomal dominant developmental disorder of the eye. Heterozygous mutations in the PAX6 gene and chromosomal rearrangements involving the 11p13 locus lie behind the pathogenesis of the AN. The key role of the PAX6 gene in the regulation of embryogenesis and the pleiotropic effect of this transcription factor explain the damage of several tissues of the anterior and posterior segments of the eye, brain structures, and the disturbance of morphogenesis and endocrine function of the pancreas observed in AN. Recently AN has been considered a syndromic pathology by several researchers. The review suggests classification and summarizes information on the clinical characteristics and genetic basis of various forms of AN. The problem of discrimination of clinical-genetic variants of the dysgenesis of the anterior segment of the eye and the differential diagnosis of PAX6-associated AN with WAGR syndrome, anterior dysgenesis, other rare monogenic and chromosomal syndromes is discussed, and the role of molecular diagnostics is emphasized.

Врожденная аниридия (ВА) — наследственный аутосомно-доминантный порок развития глаз. В основе патогенеза ВА лежат гетерозиготные мутации в гене PAX6 и хромосомные перестройки, вовлекающие локус 11p13. Ключевая роль гена PAX6 в регуляции эмбриогенеза и плейотропность действия этого транскрипционного фактора объясняют возможность поражения сразу нескольких сред переднего отрезка глаз и глазного дна, структур головного мозга, а также нарушение морфогенеза и эндокринной функции поджелудочной железы, наблюдаемые при ВА. В последнее время ВА стала рассматриваться рядом исследователей как синдромальная патология. В обзоре собраны сведения о клинической характеристике, генетической основе различных форм ВА. Обсуждается проблема дискриминации клинико-генетических вариантов дисгенезии переднего отрезка глаза и дифференциальной диагностики PAX6-ассоциированной ВА с синдромом WAGR, дисгенезиями переднего отрезка глаз, другими редкими моногенными и хромосомными синдромами; подчеркивается роль молекулярной диагностики.

congenital aniridiaWAGR syndromeanterior segment mesenchymal dysgenesisPAX6 proteindeletion 11p13врожденная аниридияWAGR-синдромдисгенезии переднего отрезка глазаPAX611p13Российский научный фонд (грант №17-15-01051)1. omim.org [Internet]. Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University [cited 2017 Jun 9]. Available from: https://omim.org/.2. Hingorani M, Moore A. Aniridia. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews®. Seattle, WA: University of Washington; 1993.3. Crolla JA, van Heyningen V. Frequent chromosome aberrations revealed by molecular cytogenetic studies in patients with aniridia. Am J Hum Genet. 2002;71(5):1138–1149. doi: 10.1086/344396.4. Gramer E, Reiter C, Gramer G. Glaucoma and frequency of ocular and general diseases in 30 patients with aniridia: a clinical study. Eur J Ophthalmol. 2012;22(1):104–110. doi: 10.5301/Ejo.2011.8318.5. Cvekl A, Callaerts P. PAX6: 25th anniversary and more to learn. Exp Eye Res. 2017;156:10–21. doi: 10.1016/j.exer.2016.04.017.6. Gronskov K, Olsen JH, Sand A, et al. Population-based risk estimates of Wilms tumor in sporadic aniridia — a comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia. Hum Genet. 2001;109(1):11–18. doi: 10.1007/s004390100529.7. Blanco-Kelly F, Villaverde-Montero C, Lorda-Sanchez I, et al. Guidelines for genetic study of aniridia. Arch Soc Esp Oftalmol. 2013;88(4):145–152. doi: 10.1016/j.oftal.2012.07.006.8. Edén U, Beijar C, Riise R, Tornqvist K. Aniridia among children and teenagers in Sweden and Norway. Acta Ophthalmol. 2008;86(7):730–734. doi: 10.1111/j.1755-3768.2008.01310.x9. Chien YH, Huang HP, Hwu WL, et al. Eye anomalies and neurological manifestations in patients with PAX6 mutations. Mol Vis. 2009;15:2139–2145.10. Netland PA, Scott ML, Boyle JW, Lauderdale JD. Ocular and systemic findings in a survey of aniridia subjects. J AAPOS. 2011;15(6):562–566. doi: 10.1016/j.jaapos.2011.07.009.11. Kokotas H, Petersen MB. Clinical and molecular aspects of aniridia. Clin Genet. 2010;77(5):409–420. doi: 10.1111/j.1399-0004.2010.01372.x.12. Park SH, Park YG, Lee MY, Kim MS. Clinical features of Korean patients with congenital aniridia. Korean J Ophthalmol. 2010;24(5):291–296. doi: 10.3341/kjo.2010.24.5.291.13. Chen P, Zang X, Sun D, et al. Mutation analysis of paired box 6 gene in inherited aniridia in northern China. Mol Vis. 2013;19:1169–1177.14. Robinson DO, Howarth RJ, Williamson KA, et al. Genetic analysis of chromosome 11p13 and the PAX6 gene in a series of 125 cases referred with aniridia. Am J Med Genet A. 2008;146A(5):558–569. doi: 10.1002/ajmg.a.32209.15. Dansault A, David G, Schwartz C, et al. Three new PAX6 mutations including one causing an unusual ophthalmic phenotype associated with neurodevelopmental abnormalities. Mol Vis. 2007;13:511–523.16. Taylor D, Hoyt CS. Practical paediatric ophthalmology. Cambridge, USA: Wiley; 1997.17. Lee H, Khan R, O’Keefe M. Aniridia: current pathology and management. Acta Ophthalmol. 2008;86(7):708–715. doi: 10.1111/j.1755-3768.2008.01427.x.18. Kasmann-Kellner B, Seitz B. [Aniridia syndrome: clinical findings, problematic courses and suggestions for optimization of care («aniridia guide»). (In German).] Ophthalmologe. 2014;111(12):1145–1156. doi: 10.1007/s00347-014-3060-x.19. Schanilec P, Biernacki R. Aniridia: a comparative overview. Am Orthopt J. 2014;64:98–104. doi: 10.3368/aoj.64.1.98.20. Hingorani M, Hanson I, van Heyningen V. Aniridia. Eur J Hum Genet. 2012;20(10):1011–1017. doi: 10.1038/ejhg.2012.100.21. Hingorani M, Williamson KA, Moore AT, van Heyningen V. Detailed ophthalmologic evaluation of 43 individuals with PAX6 mutations. Invest Ophthalmol Vis Sci. 2009;50(6):2581–2590. doi: 10.1167/iovs.08-2827.22. Lee NY, Lee YE, Mok J, et al. Three cases with unusual ophthalmic phenotypes of congenital aniridia. Can J Ophthalmol. 2013;48(4):340–342. doi: 10.1016/j.jcjo.2013.02.009.23. Elsas FJ, Maumenee IH, Kenyon KR, Yoder F. Familial aniridia with preserved ocular function. Am J Ophthalmol. 1977;83(5):718–724. doi: 10.1016/0002-9394(77)90139-8.24. Hittner HM, Riccardi VM, Ferrell RE, et al. Variable expressivity in autosomal dominant aniridia by clinical, electrophysiologic, and angiographic criteria. Am J Ophthalmol. 1980;89(4):531–539. doi: 10.1016/0002-9394(80)90062-8.25. Tremblay F, Gupta SK, De Becker I, et al. Effects of PAX6 mutations on retinal function: an electroretinographic study. Am J Ophthalmol. 1998;126(2):211–218. doi: 10.1016/S0002-9394(98)00190-1.26. Hood MP, Kerr NC, Smaoui N, Iannaccone A. Abnormal cone ERGs in a family with congenital nystagmus and photophobia harboring a p.X423Lfs mutation in the PAX6 gene. Doc Ophthalmol. 2015;130(2):157–164. doi: 10.1007/s10633-014-9477-3.27. Bamiou DE, Free SL, Sisodiya SM, et al. Auditory interhemispheric transfer deficits, hearing difficulties, and brain magnetic resonance imaging abnormalities in children with congenital aniridia due to PAX6 mutations. Arch Pediatr Adolesc Med. 2007;161(5):463–469. doi: 10.1001/archpedi.161.5.463.28. Davis LK, Meyer KJ, Rudd DS, et al. Pax6 3′ deletion results in aniridia, autism and mental retardation. Hum Genet. 2008;123(4):371–378. doi: 10.1007/s00439-008-0484-x.29. Malandrini A, Mari F, Palmeri S, et al. PAX6 mutation in a family with aniridia, congenital ptosis, and mental retardation. Clin Genet. 2001;60(2):151–154. doi: 10.1034/j.1399-0004.2001.600210.x.30. Graziano C, D’Elia AV, Mazzanti L, et al. A de novo nonsense mutation of PAX6 gene in a patient with aniridia, ataxia, and mental retardation. Am J Med Genet A. 2007;143A(15):1802–1805. doi: 10.1002/ajmg.a.31808.31. Hanish AE, Butman JA, Thomas F, et al. Pineal hypoplasia, reduced melatonin and sleep disturbance in patients with PAX6 haploinsufficiency. J Sleep Res. 2016;25(1):16–22. doi: 10.1111/jsr.12345.32. Mitchell TN, Free SL, Williamson KA, et al. Polymicrogyria and absence of pineal gland due to PAX6 mutation. Ann Neurol. 2003;53(5):658–663. doi: 10.1002/ana.10576.33. Thompson PJ, Mitchell TN, Free SL, et al. Cognitive functioning in humans with mutations of the PAX6 gene. Neurology. 2004;62(7):1216–1218. doi: 10.1212/01.wnl.0000118298.81140.62.34. Yogarajah M, Matarin M, Vollmar C, et al. PAX6, brain structure and function in human adults: advanced MRI in aniridia. Ann Clin Transl Neurol. 2016;3(5):314–330. doi: 10.1002/acn3.297.35. Heyman I, Frampton I, van Heyningen V, et al. Psychiatric disorder and cognitive function in a family with an inherited novel mutation of the developmental control gene PAX6. Psychiatr Genet. 1999;9(2):85–90. doi: 10.1097/00041444-199906000-00006.36. Ellison-Wright Z, Heyman I, Frampton I, et al. Heterozygous PAX6 mutation, adult brain structure and fronto-striato-thalamic function in a human family. Eur J Neurosci. 2004;19(6):1505–1512. doi: 10.1111/j.1460-9568.2004.03236.x.37. Yasuda T, Kajimoto Y, Fujitani Y, et al. PAX6 mutation as a genetic factor common to aniridia and glucose intolerance. Diabetes. 2002;51(1):224–230. doi: 10.2337/diabetes.51.1.224.38. Shimo N, Yasuda T, Kitamura T, et al. Aniridia with a heterozygous PAX6 mutation in which the pituitary function was partially impaired. Intern Med. 2014;53(1):39–42. doi: 10.2169/internalmedicine.53.1184.39. Nishi M, Sasahara M, Shono T, et al. A case of novel de novo paired box gene 6 (PAX6) mutation with early-onset diabetes mellitus and aniridia. Diabet Med. 2005;22(5):641–644. doi: 10.1111/j.1464-5491.2005.01469.x.40. Fraumeni JF Jr, Glass AG. Wilms’ tumor and congenital aniridia. JAMA. 1968;206(4):825–828. doi: 10.1001/jama.1968.03150040037007.41. Breslow NE, Norris R, Norkool PA, et al. Characteristics and outcomes of children with the Wilms Tumor-Aniridia syndrome: a report from the National Wilms Tumor Study Group. J Clin Oncol. 2003;21(24):4579–4585. doi: 10.1200/Jco.2003.06.096.42. Clericuzio C, Hingorani M, Crolla JA, et al. Clinical utility gene card for: WAGR syndrome. Eur J Hum Genet. 2011;19(4). doi: 10.1038/ejhg.2010.220.43. Haicken BN, Miller DR. Simultaneous occurrence of congenital aniridia, hamartoma, and Wilms’ tumor. J Pediatr. 1971;78(3):497–502. doi: 10.1016/s0022-3476(71)80233-0.44. Тератология человека. Руководство для врачей / Под ред. Лазюка Г.И. 2-е изд., перераб. и доп. ― М.: Медицина; 1991. ― 480 с. [Teratologiya cheloveka. Rukovodstvo dlya vrachei. Ed by Lazyuk GI. 2nd ed., revised and enlarged. Moscow: Meditsina; 1991. 480 p. (In Russ).]45. Yamamoto T, Togawa M, Shimada S, et al. Narrowing of the responsible region for severe developmental delay and autistic behaviors in WAGR syndrome down to 1.6 Mb including PAX6, WT1, and PRRG4. Am J Med Genet A. 2014;164A(3):634–638. doi: 10.1002/ajmg.a.36325.46. Bremond-Gignac D, Gerard-Blanluet M, Copin H, et al. Three patients with hallucal polydactyly and WAGR syndrome, including discordant expression of Wilms tumor in MZ twins. Am J Med Genet A. 2005;134(4):422–425. doi: 10.1002/ajmg.a.30646.47. Scott DA, Cooper ML, Stankiewicz P, et al. Congenital diaphragmatic hernia in WAGR syndrome. Am J Med Genet A. 2005;134(4):430–433. doi: 10.1002/ajmg.a.30654.48. Fischbach BV, Trout KL, Lewis J, et al. WAGR syndrome: a clinical review of 54 cases. Pediatrics. 2005;116(4):984–988. doi: 10.1542/peds.2004-0467.49. Miura R, Yokoyama Y, Shigeto T, et al. Dysgerminoma developing from an ectopic ovary in a patient with WAGR syndrome: a case report. Mol Clin Oncol. 2016;5(5):503–506. doi: 10.3892/mco.2016.1004.50. Churchill A, Booth A. Genetics of aniridia and anterior segment dysgenesis. Br J Ophthalmol. 1996;80(7):669–673. doi: 10.1136/bjo.80.7.669.51. Cheong SS, Hentschel L, Davidson AE, et al. Mutations in CPAMD8 cause a unique form of autosomal-recessive anterior segment dysgenesis. Am J Hum Genet. 2016;99(6):1338–1352. doi: 10.1016/j.ajhg.2016.09.022.52. Choi A, Lao R, Ling-Fung Tang P, et al. Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis. Eur J Hum Genet. 2015;23(3):337–341. doi: 10.1038/ejhg.2014.119.53. Gould DB, John SW. Anterior segment dysgenesis and the developmental glaucomas are complex traits. Hum Mol Genet. 2002;11(10):1185–1193. doi: 10.1093/hmg/11.10.1185.54. Sowden JC. Molecular and developmental mechanisms of anterior segment dysgenesis. Eye (Lond). 2007;21(10):1310–1318. doi: 10.1038/sj.eye.6702852.55. Nanjo Y, Kawasaki S, Mori K, et al. A novel mutation in the alternative splice region of the PAX6 gene in a patient with Peters’ anomaly. Br J Ophthalmol. 2004;88(5):720–721.56. Hanson IM, Fletcher JM, Jordan T, et al. Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters’ anomaly. Nat Genet. 1994;6(2):168–173. doi: 10.1038/ng0294-168.57. Riise R, Storhaug K, Brondum-Nielsen K. Rieger syndrome is associated with PAX6 deletion. Acta Ophthalmol Scand. 2001;79(2):201–203. doi: 10.1034/j.1600-0420.2001.079002201.x.58. Hanson I, Churchill A, Love J, et al. Missense mutations in the most ancient residues of the PAX6 paired domain underlie a spectrum of human congenital eye malformations. Hum Mol Genet. 1999;8(2):165–172. doi: 10.1093/hmg/8.2.165.59. Willcock C, Grigg J, Wilson M, et al. Congenital iris ectropion as an indicator of variant aniridia. Br J Ophthalmol. 2006;90(5):658–659. doi: 10.1136/bjo.2005.089698.60. Miller RW, Fraumeni JF Jr, Manning MD. Association of Wilms’s tumor with aniridia, hemihypertrophy and other congenital malformations. N Engl J Med. 1964;270:922–927. doi: 10.1056/NEJM196404302701802.61. Gessler M, Bruns GA. A physical map around the WAGR complex on the short arm of chromosome 11. Genomics. 1989;5(1):43–55. doi: 10.1016/0888-7543(89)90084-0.62. Hossain A, Saunders GF. The human sex-determining gene SRY is a direct target of WT1. J Biol Chem. 2001;276(20):16817–16823. doi: 10.1074/jbc.M009056200.63. Wagner KD, Wagner N, Schley G, et al. The Wilms’ tumor suppressor Wt1 encodes a transcriptional activator of the class IV POU-domain factor Pou4f2 (Brn-3b). Gene. 2003;305(2):217–223. doi: 10.1016/S0378-1119(02)01231-3.64. Han JC, Thurm A, Golden Williams C, et al. Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome. Cortex. 2013;49(10):2700–2710. doi: 10.1016/j.cortex.2013.02.009.65. Xu S, Han JC, Morales A, et al. 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(2):181–187. doi: 10.1159/000172086.66. Franke U, Riccardi VM, Hittner HM, Borges W. Interstitial del(11p) as a cause of the aniridia-Wilms tumor association: band localization and a heritable basis. (Abstract) Am J Hum Genet. 1978;30(6):A81.67. Beckwith JB. Nephrogenic rests and the pathogenesis of Wilms tumor: developmental and clinical considerations. Am J Med Genet. 1998;79(4):268–273. doi: 10.1002/(Sici)1096-8628(19981002)79:4<268::Aid-Ajmg7>3.0.Co;2-I.68. Turleau C, de Grouchy J, Dufier JL, et al. Aniridia, male pseudohermaphroditism, gonadoblastoma, mental retardation, and del 11p13. Hum Genet. 1981;57(3):300–306. doi: 10.1007/BF00278949.69. Junien C, Turleau C, Grouchy JD, et al. Regional assignment of catalase (CAT) gene to band 11p13. Association with the aniridia-Wilms’ tumor-Gonadoblastoma (WAGR) complex. Ann Genet. 1980;23(3):165–168.70. Le Caignec C, Delnatte C, Vermeesch JR, et al. Complete sex reversal in a WAGR syndrome patient. Am J Med Genet A. 2007;143A(22):2692–2695. doi: 10.1002/ajmg.a.31997.71. Turleau C, de Grouchy J, Nihoul-Fékété C, et al. Del11p13/nephroblastoma without aniridia. Hum Genet. 1984;67(4):455–456. doi: 10.1007/Bf00291410.72. Han JC, Liu QR, Jones M, et al. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med. 2008;359(9):918–927. doi: 10.1056/NEJMoa0801119.73. Gilgenkrantz S, Vigneron C, Gregoire MJ, et al. Association of del(11)(p15.1p12), aniridia, catalase deficiency, and cardiomyopathy. Am J Med Genet. 1982;13(1):39–49. doi: 10.1002/ajmg.1320130108.74. Maurer HS, Pendergrass TW, Borges W, Honig GR. The role of genetic factors in the etiology of Wilms’ tumor: two pairs of monozygous twins with congenital abnormalities (aniridia; hemihypertrophy) and discordance for Wilms’ tumor. Cancer. 1979;43(1):205–208. doi: 10.1002/1097-0142(197901)43:1<205::AID-CNCR2820430130>3.0.CO;2-775. Bartholdi D, Krajewska-Walasek M, Ounap K, et al. Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS-like phenotypes. J Med Genet. 2009;46(3):192–197. doi: 10.1136/jmg.2008.061820.76. 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(10):823-824. doi: 10.1136/jmg.32.10.823.77. Bremond-Gignac D, Crolla JA, Copin H, et al. Combination of WAGR and Potocki-Shaffer contiguous deletion syndromes in a patient with an 11p11.2-p14 deletion. Eur J Hum Genet. 2005;13(4):409–413. doi: 10.1038/sj.ejhg.5201358.78. Ticho BH, Hilchie-Schmidt C, Egel RT, et al. Ocular findings in Gillespie-like syndrome: association with a new PAX6 mutation. Ophthalmic Genet. 2006;27(4):145–149. doi: 10.1080/13816810600976897.79. McEntagart M, Williamson KA, Rainger JK, et al. A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominant-negative effect. Am J Hum Genet. 2016;98(5):981–992. doi: 10.1016/j.ajhg.2016.03.018.80. Gerber S, Alzayady KJ, Burglen L, et al. Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome. Am J Hum Genet. 2016;98(5):971–980. doi: 10.1016/j.ajhg.2016.03.004.81. Verloes A, Narcy F, Grattagliano B, et al. Osteocraniostenosis. J Med Genet. 1994;31(10):772–778. doi: 10.1136/jmg.31.10.772.82. Verloes A, Temple IK, Bonnet S, Bottani A. Coloboma, mental retardation, hypogonadism, and obesity: Critical review of the so-called Biemond syndrome type 2, updated nosology, and delineation of three "new" syndromes. Am J Med Genet. 1997;69(4):370–379. doi: 10.1002/(Sici)1096-8628(19970414)69:4<370::Aid-Ajmg7>3.0.Co;2-P.83. Weber FM, Dooley RR, Sparkes RS. Anal atresia, eye anomalies, and an additional small abnormal acrocentric chromosome (47,XX,mar+): report of a case. J Pediatr. 1970;76(4):594–597. doi: 10.1016/s0022-3476(70)80410-3.84. Chitayat D, Hahm SY, Iqbal MA, Nitowsky HM. Ring chromosome 6: report of a patient and literature review. Am J Med Genet. 1987;26(1):145–151. doi: 10.1002/ajmg.1320260122.85. Nelson LB, Spaeth GL, Nowinski TS, et al. Aniridia. A review. Surv Ophthalmol. 1984;28(6):621–642. doi: 10.1016/0039-6257(84)90184-x.86. Sachdev MS, Sood NN, Kumar H, Ghose S. Bilateral aniridia with Marfan’s syndrome and dental anomalies ― a new association. Jpn J Ophthalmol. 1986;30(4):360–366.87. Sheehan WJ, Delmonte OM, Miller DT, et al. Novel presentation of Omenn syndrome in association with aniridia. J Allergy Clin Immunol. 2009;123(4):966–969. doi: 10.1016/j.jaci.2008.12.007.88. Ohno F, Yamano T, Kataoka K. A case of congenital aniridia and familial pheochromocytoma with special reference to aniridia-Wilms’ tumor syndrome. Jinrui Idengaku Zasshi. 1982;27(4):335–340. doi: 10.1007/bf01900445.89. Castori M, Barboni L, Duncan PJ, et al. Darier disease, multiple bone cysts, and aniridia due to double de novo heterozygous mutations in ATP2A2 and PAX6. Am J Med Genet A. 2009;149A(8):1768–1772. doi: 10.1002/ajmg.a.32960.90. Yamamoto Y, Hayasaka S, Setogawa T. Family with aniridia, microcornea, and spontaneously reabsorbed cataract. Arch Ophthalmol. 1988;106(4):502–504. doi: 10.1001/archopht.1988.01060130548033.91. Vadiakas G, Oulis C, Tsianos E, Mavridou S. A typical Hallermann-Streiff syndrome in a 3 year old child. J Clin Pediatr Dent. 1995;20(1):63–68.92. Schanzlin DJ, Goldberg DB, Brown SI. Hallermann-Streiff syndrome associated with sclerocornea, aniridia, and a chromosomal abnormality. Am J Ophthalmol. 1980;90(3):411–415. doi: 10.1016/s0002-9394(14)74926-8.93. Mirkinson AE, Mirkinson NK. A familial syndrome of aniridia and absence of the patella. Birth Defects Orig Artic Ser. 1975;11(5):129–131.94. Sato H, Takaya K, Nihira S, Fujita H. Familial mental retardation associated with balanced chromosome rearrangement rcp t(8;11)(q24.3;p15.1). J Med Genet. 1989;26(10):642–644. doi: 10.1136/jmg.26.10.642.