Врожденная аниридия в педиатрической практике

Суханова Н.В., Геворкян А.К., Васильева Т.А., Марахонов А.В., Зинченко Р.А., Катаргина Л.А. Врожденная аниридия в педиатрической практике. Педиатрия. Consilium Medicum. 2024;4:373–378. DOI: 10.26442/26586630.2024.4.203088

© ООО «КОНСИЛИУМ МЕДИКУМ», 2024 г.

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Sukhanova NV, Gevorkyan AK, Vasilyeva TA, Marakhonov AV, Zinchenko RA, Katargina LA. Congenital aniridia in pediatric practice: A review. Pediatrics. Consilium Medicum. 2024;4:373–378. DOI: 10.26442/26586630.2024.4.203088

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Аннотация

Врожденная аниридия (ВА) – редкое врожденное генетическое заболевание. В настоящее время насчитывается более 20 врожденных наследственных (хромосомных и моногенных) синдромов с ВА. ВА разделяется на несиндромальную форму, которая затрагивает все структуры глаза (75% случаев) и синдромальную (20%, включая WAGR-синдром). Синдромальные формы аниридии включают: ВА, отягощенную поражением центральной нервной системы, эндокринной, мочеполовой и других систем и органов (<10%); синдром WAGR (<10%) и нетипичные редкие формы ВА, возникающие на фоне других сложных моногенных или хромосомных патологий. Сложность при проведении подтверждающей ДНК-диагностики ВА обусловлена разнообразием причин, которые приводят к повреждению функции гена PAX6 (внутригенные мутации гена PAX6 и крупные хромосомные перестройки с вовлечением хромосомного региона 11p13). У пациентов с ВА есть необходимость в комплексном подходе, включающем как раннюю диагностику, так и коррекцию возникших осложнений. Офтальмологи и педиатры сталкиваются с проблемой прогнозирования течения заболевания, так как существуют различные вариации состояния структур и функций глаза и сопутствующей патологии с самого рождения, а также разнообразие их динамики, которая обусловлена как генетическими факторами, так и адекватностью лечебно-профилактических мероприятий. В статье представлены эпидемиология, офтальмологические данные и связанные с этим расстройством синдромы, а также последние достижения генетики, касающиеся проблемы ВА. Также описана маршрутизация медицинского сопровождения пациентов с ВА, в которой один врач-педиатр или специалист, занимающийся проблемами слабовидения, обладающий знаниями о ВА и работающий совместно с узкопрофильными специалистами, наблюдает и ведет пациента в течение многих лет.

Ключевые слова: врожденная аниридия, дети, ген PAX6, ген WT1, синдром WAGR

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Congenital aniridia (CA) is a rare congenital genetic disorder. Currently, more than 20 congenital hereditary (chromosomal and monogenic) syndromes include CA. It is divided into a nonsyndromic type involving all eye structures (75% of cases) and a syndromic type (20%, including WAGR syndrome). The syndromic types of aniridia include CA aggravated by the involvement of the central nervous system, endocrine, genitourinary, and other systems and organs (<10%); WAGR syndrome (<10%) and atypical rare forms of CA that occur with other complex monogenic or chromosomal diseases. The difficulty in identifying and confirming CA using DNA-based diagnostic methods is due to multiple causes that lead to the PAX6 gene dysfunction (intragenic PAX6 mutations and large chromosomal rearrangements involving the 11p13 chromosomal region). Patients with CA require a comprehensive approach, including both early diagnosis and treatment of complications. Ophthalmologists and pediatricians face the problem of predicting the disease course since there are many variations in the state of structures and functions of the eye and comorbidities since birth, as well as the diversity of their course, which is due to both genetic factors and the adequacy of therapeutic and preventive measures. The article presents epidemiology, ophthalmic examination data, related syndromes, and the latest advances in genetics related to CA. It also describes the routing of medical support for patients with CA, in which a single pediatrician or a specialist who deals with problems of visual impairment, who has knowledge of CA and works with a specialized team, observes and manages the patient for many years.

Keywords: congenital aniridia, children, PAX6 gene, WT1 gene, WAGR syndrome

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Список литературы

1. Аниридия врожденная. Клинические рекомендации. 2022. Режим доступа: https://cr.minzdrav.gov.ru/recomend/740_1. Ссылка активна на 08.06.2024 [Congenital aniridia. Clinical guidelines. 2022. Available at: Accessed: 08.06.2024 (in Russian)].
2. Hingorani M, Williamson KA, Moore AT, van Heyningen V. Detailed ophthalmologic evaluation of 43 individuals with pax6 mutations. Investig Ophthalmol Vis Sci. 2009;50:2581-90. DOI:10.1167/iovs.08-2827
3. Tzoulaki I, White IM, Hanson IM. Pax6 mutations: Genotype-phenotype correlations. BMC Genet. 2005;6:27. DOI:10.1186/1471-2156-6-27
4. Kleinjan DA, Seawright A, Mella S, et al. Long-range downstream enhancers are essential for pax6 expression. Dev Biol. 2006;299:563-81.
5. Damian A, Nunez-Moreno G, Jubin C, et al. Long-read genome sequencing identifies cryptic structural variants in congenital aniridia cases. Hum Genom. 2023;17:45. DOI:10.1186/s40246-023-00490-8
6. Fischbach BV, Trout KL, Lewis J, et al. Wagr syndrome: A clinical review of 54 cases. Pediatrics. 2005;116:984-8.
7. Vasilyeva TA, Marakhonov AV, Voskresenskaya AA, et al. Epidemiology of PAX6 Gene Pathogenic Variants and Expected Prevalence of PAX6-Associated Congenital Aniridia across the Russian Federation: A Nationwide Study. Genes (Basel). 2023;14(11):2041.
8. Hall HN, Williamson KA, FitzPatrick DR. The genetic architecture of aniridia and Gillespie syndrome. Human Genet. 2019;138(8-9):881-98.
9. Miesfeld JB, Brown NL. Eye organogenesis: A hierarchical view of ocular development. Curr Topics Developmental Biol. 2019;132:351-93.
10. Graw J. Eye development. Current topics in developmental biology. 2010;90:343-86.
11. Bloom J, Motlagh M, Czyz CN. Anatomy, Head and Neck, Eye Iris Sphincter Muscle. 2021. Available at: https://www.ncbi.nlm.nih.gov/books/NBK532252/. Accessed: 15.07.2024.
12. Cvekl A, Callaerts P. PAX6: 25th anniversary and more to learn. Experiment Eye Res. 2017;156:10-21.
13. Jin X, Liu W, Qv L, et al. A novel variant in PAX6 as the cause of aniridia in a Chinese family. BMC Ophthalmol. 2021;21(1).
14. Ito YA, Footz TK, Berry FB, et al. Severe molecular defects of a novel FOXC1 W152G mutation result in aniridia. Investig Ophthalmol Visual Sci. 2009;50(8):3573-9.
15. Perveen R, Lloyd IC, Clayton-Smith J, et al. Phenotypic variability and asymmetry of Rieger syndrome associated with PITX2 mutations. Investig Ophthalmol Visual Sci. 2000;41(9):2456-60.
16. De Silva D, Williamson KA, Dayasiri KC, et al. Gillespie syndrome in a South Asian child: a case report with confirmation of a heterozygous mutation of the ITPR1 gene and review of the clinical and molecular features. BMC Pediatr. 2018;18(1):308.
17. Chen SN, Wang YQ, Hao CL, et al. Multisystem smooth muscle dysfunction syndrome in a Chinese girl: A case report and review of the literature. World J Clin Cases. 2019;7(24):4355-65.
18. Lee H, Khan R, O’keefe M. Aniridia: current pathology and management. Acta Ophthalmologica. 2008;86(7):708-15.
19. Moosajee M, Hingorani M, Moore AT. PAX6-Related Aniridia. GeneReviews®. 2018. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1360/. Accessed: 15.07.2024.
20. Hanson IM. PAX6 and congenital eye malformations. Pediatric Res. 2003;54(6):791-6.
21. Vasilyeva TA, Voskresenskaya AA, Käsmann-Kellner B, et al. Molecular analysis of patients with aniridia in Russian Federation broadens the spectrum of PAX6 mutations. Clin Genet. 2017;92(6):639-44.
22. Lim HT, Kim DH, Kim H. PAX6 aniridia syndrome: clinics, genetics, and therapeutics. Curr Opin Ophthalmol. 2017;28(5):436-47. DOI:10.1097/ICU.0000000000000405
23. 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. Part A. 2008;146A(5):558-69.
24. Chen TC, Walton DS. Goniosurgery for prevention of aniridic glaucoma. Arch Ophthalmol. 1999;117(9):1144-8.
25. Ferreira MAT, de Almeida Júnior IG, Kuratani DK, et al. WAGRO syndrome: a rare genetic condition associated with aniridia and additional ophthalmologic abnormalities. Arquivos brasileiros de oftalmologia. 2019;82(4):336-8.
26. Han JC, Liu QR, Jones M, et al. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. New Engl J Med. 2008;359(9):918-27.
27. Brémond-Gignac D, Crolla JA, Guichet A, et al. Combination of WAGR and Potocki-Shaffer contiguous deletion syndromes in a patient with an 11p11.2-p14 deletion. Eur J Human Genet. 2005;13(4):409-13.
28. Sharan S, Mirzayans F, Footz T, et al. Elliptical anterior iris stromal defects associated with PAX6 gene sequence changes. J AAPOS. 2008;12(4):340-3.
29. Willcock C, Grigg J, Wilson M, et al. Congenital iris ectropion as an indicator of variant aniridia. British J Ophthalmol. 2006;90(5):658-9.
30. Shaham O, Menuchin Y, Farhy C, Ashery-Padan R. Pax6: a multi-level regulator of ocular development. Progress Retinal Eye Res. 2012;31(5):351-76.
31. D’Oria, Barraquer FR, Alio JL. Crystalline lens alterations in congenital aniridia. Archivos de la Sociedad Espanola de Oftalmologia. 2021;96:38-51.
32. Khaw PT, Walton D, Maul E. Aniridia. J Glaucoma. 2002;11(2):164-8.
33. Hingorani M, Hanson I, Van Heyningen V. Aniridia. Eur J Human Genet. 2012;20(10):1011-7.
34. Abouzeid H, Youssef MA, ElShakankiri N, et al. PAX6 aniridia and interhemispheric brain anomalies. Mol Vision. 2009;15:2074-83.
35. Shinawi M, Sahoo T, Maranda B, et al. 11p14.1 microdeletions associated with ADHD, autism, developmental delay, and obesity. Am J Med Genet. Part A. 2011;155A(6):1272-80.
36. Sisodiya SM, Free SL, Williamson KA, et al. PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans. Nature Genet. 2001;28(3):214-6.
37. 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 Adolescent Med. 2007;161(5):463-9.
38. Mitchell TN, Free SL, Williamson KA, et al. Polymicrogyria and absence of pineal gland due to PAX6 mutation. Ann Neurol. 2003;53(5):658-63.
39. Landsend ECS, Lagali N, Utheim TP. Congenital aniridia – A comprehensive review of clinical features and therapeutic approaches. Surv Ophthalmol. 2021;66(6):1031-50.
40. 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. Diabetic Med J. 2005;22(5):641-4.
41. Sadagopan KA, Liu GT, Capasso JE, et al. Anirdia-like phenotype caused by 6p25 dosage aberrations. Am J Med Genet. Part A. 2015;167A(3):524-8.
42. McEntagart M, Williamson A, 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):981-92.
43. Roulez FMJ, Faes F, Delbeke P, et al. Congenital fixed dilated pupils due to ACTA2- multisystemic smooth muscle dysfunction syndrome. J Neuroophthalmol. 2014;34(2):137-43.
44. Seifi M, Walter MA. Axenfeld-Rieger syndrome. Clin Genet. 2018;93(6):1123-30.
45. Jesina D. Alagille Syndrome: An Overview. Neonatal Network. 2017;36(6):343-7.

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1. Congenital aniridia. Clinical guidelines. 2022. Available at: Accessed: 08.06.2024 (in Russian).
2. Hingorani M, Williamson KA, Moore AT, van Heyningen V. Detailed ophthalmologic evaluation of 43 individuals with pax6 mutations. Investig Ophthalmol Vis Sci. 2009;50:2581-90. DOI:10.1167/iovs.08-2827
3. Tzoulaki I, White IM, Hanson IM. Pax6 mutations: Genotype-phenotype correlations. BMC Genet. 2005;6:27. DOI:10.1186/1471-2156-6-27
4. Kleinjan DA, Seawright A, Mella S, et al. Long-range downstream enhancers are essential for pax6 expression. Dev Biol. 2006;299:563-81.
5. Damian A, Nunez-Moreno G, Jubin C, et al. Long-read genome sequencing identifies cryptic structural variants in congenital aniridia cases. Hum Genom. 2023;17:45. DOI:10.1186/s40246-023-00490-8
6. Fischbach BV, Trout KL, Lewis J, et al. Wagr syndrome: A clinical review of 54 cases. Pediatrics. 2005;116:984-8.
7. Vasilyeva TA, Marakhonov AV, Voskresenskaya AA, et al. Epidemiology of PAX6 Gene Pathogenic Variants and Expected Prevalence of PAX6-Associated Congenital Aniridia across the Russian Federation: A Nationwide Study. Genes (Basel). 2023;14(11):2041.
8. Hall HN, Williamson KA, FitzPatrick DR. The genetic architecture of aniridia and Gillespie syndrome. Human Genet. 2019;138(8-9):881-98.
9. Miesfeld JB, Brown NL. Eye organogenesis: A hierarchical view of ocular development. Curr Topics Developmental Biol. 2019;132:351-93.
10. Graw J. Eye development. Current topics in developmental biology. 2010;90:343-86.
11. Bloom J, Motlagh M, Czyz CN. Anatomy, Head and Neck, Eye Iris Sphincter Muscle. 2021. Available at: https://www.ncbi.nlm.nih.gov/books/NBK532252/. Accessed: 15.07.2024.
12. Cvekl A, Callaerts P. PAX6: 25th anniversary and more to learn. Experiment Eye Res. 2017;156:10-21.
13. Jin X, Liu W, Qv L, et al. A novel variant in PAX6 as the cause of aniridia in a Chinese family. BMC Ophthalmol. 2021;21(1).
14. Ito YA, Footz TK, Berry FB, et al. Severe molecular defects of a novel FOXC1 W152G mutation result in aniridia. Investig Ophthalmol Visual Sci. 2009;50(8):3573-9.
15. Perveen R, Lloyd IC, Clayton-Smith J, et al. Phenotypic variability and asymmetry of Rieger syndrome associated with PITX2 mutations. Investig Ophthalmol Visual Sci. 2000;41(9):2456-60.
16. De Silva D, Williamson KA, Dayasiri KC, et al. Gillespie syndrome in a South Asian child: a case report with confirmation of a heterozygous mutation of the ITPR1 gene and review of the clinical and molecular features. BMC Pediatr. 2018;18(1):308.
17. Chen SN, Wang YQ, Hao CL, et al. Multisystem smooth muscle dysfunction syndrome in a Chinese girl: A case report and review of the literature. World J Clin Cases. 2019;7(24):4355-65.
18. Lee H, Khan R, O’keefe M. Aniridia: current pathology and management. Acta Ophthalmologica. 2008;86(7):708-15.
19. Moosajee M, Hingorani M, Moore AT. PAX6-Related Aniridia. GeneReviews®. 2018. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1360/. Accessed: 15.07.2024.
20. Hanson IM. PAX6 and congenital eye malformations. Pediatric Res. 2003;54(6):791-6.
21. Vasilyeva TA, Voskresenskaya AA, Käsmann-Kellner B, et al. Molecular analysis of patients with aniridia in Russian Federation broadens the spectrum of PAX6 mutations. Clin Genet. 2017;92(6):639-44.
22. Lim HT, Kim DH, Kim H. PAX6 aniridia syndrome: clinics, genetics, and therapeutics. Curr Opin Ophthalmol. 2017;28(5):436-47. DOI:10.1097/ICU.0000000000000405
23. 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. Part A. 2008;146A(5):558-69.
24. Chen TC, Walton DS. Goniosurgery for prevention of aniridic glaucoma. Arch Ophthalmol. 1999;117(9):1144-8.
25. Ferreira MAT, de Almeida Júnior IG, Kuratani DK, et al. WAGRO syndrome: a rare genetic condition associated with aniridia and additional ophthalmologic abnormalities. Arquivos brasileiros de oftalmologia. 2019;82(4):336-8.
26. Han JC, Liu QR, Jones M, et al. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. New Engl J Med. 2008;359(9):918-27.
27. Brémond-Gignac D, Crolla JA, Guichet A, et al. Combination of WAGR and Potocki-Shaffer contiguous deletion syndromes in a patient with an 11p11.2-p14 deletion. Eur J Human Genet. 2005;13(4):409-13.
28. Sharan S, Mirzayans F, Footz T, et al. Elliptical anterior iris stromal defects associated with PAX6 gene sequence changes. J AAPOS. 2008;12(4):340-3.
29. Willcock C, Grigg J, Wilson M, et al. Congenital iris ectropion as an indicator of variant aniridia. British J Ophthalmol. 2006;90(5):658-9.
30. Shaham O, Menuchin Y, Farhy C, Ashery-Padan R. Pax6: a multi-level regulator of ocular development. Progress Retinal Eye Res. 2012;31(5):351-76.
31. D’Oria, Barraquer FR, Alio JL. Crystalline lens alterations in congenital aniridia. Archivos de la Sociedad Espanola de Oftalmologia. 2021;96:38-51.
32. Khaw PT, Walton D, Maul E. Aniridia. J Glaucoma. 2002;11(2):164-8.
33. Hingorani M, Hanson I, Van Heyningen V. Aniridia. Eur J Human Genet. 2012;20(10):1011-7.
34. Abouzeid H, Youssef MA, ElShakankiri N, et al. PAX6 aniridia and interhemispheric brain anomalies. Mol Vision. 2009;15:2074-83.
35. Shinawi M, Sahoo T, Maranda B, et al. 11p14.1 microdeletions associated with ADHD, autism, developmental delay, and obesity. Am J Med Genet. Part A. 2011;155A(6):1272-80.
36. Sisodiya SM, Free SL, Williamson KA, et al. PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans. Nature Genet. 2001;28(3):214-6.
37. 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 Adolescent Med. 2007;161(5):463-9.
38. Mitchell TN, Free SL, Williamson KA, et al. Polymicrogyria and absence of pineal gland due to PAX6 mutation. Ann Neurol. 2003;53(5):658-63.
39. Landsend ECS, Lagali N, Utheim TP. Congenital aniridia – A comprehensive review of clinical features and therapeutic approaches. Surv Ophthalmol. 2021;66(6):1031-50.
40. 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. Diabetic Med J. 2005;22(5):641-4.
41. Sadagopan KA, Liu GT, Capasso JE, et al. Anirdia-like phenotype caused by 6p25 dosage aberrations. Am J Med Genet. Part A. 2015;167A(3):524-8.
42. McEntagart M, Williamson A, 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):981-92.
43. Roulez FMJ, Faes F, Delbeke P, et al. Congenital fixed dilated pupils due to ACTA2- multisystemic smooth muscle dysfunction syndrome. J Neuroophthalmol. 2014;34(2):137-43.
44. Seifi M, Walter MA. Axenfeld-Rieger syndrome. Clin Genet. 2018;93(6):1123-30.
45. Jesina D. Alagille Syndrome: An Overview. Neonatal Network. 2017;36(6):343-7.

Авторы

Н.В. Суханова*¹, А.К. Геворкян^2,3, Т.А. Васильева⁴, А.В. Марахонов⁴, Р.А. Зинченко⁴, Л.А. Катаргина⁵

¹ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия;
²ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России, Москва, Россия;
³ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия;
⁴ФГБНУ «Медико-генетический научный центр им. акад. Н.П. Бочкова», Москва, Россия;
⁵ФГБОУ «Национальный медицинский исследовательский центр глазных болезней им. Гельмгольца» Минздрава России, Москва, Россия
*natelasukhanova@gmail.com

________________________________________________

Natella V. Sukhanova*¹, Anait K. Gevorkyan^2,3, Tatyana A. Vasilyeva⁴, Andrey V. Marakhonov⁴, Rena A. Zinchenko⁴, Ludmila A. Katargina⁵

¹Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia;
²Pirogov Russian National Research Medical University, Moscow, Russia;
³Russian Medical Academy of Continuous Professional Education, Moscow, Russia;
⁴Bochkov Research Centre for Medical Genetics, Moscow, Russia;
⁵Helmholtz National Medical Research Center for Eye Diseases, Moscow, Russia
*natelasukhanova@gmail.com

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