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LMX1B-ассоциированный стероид-резистентный нефротический синдром c фокально-сегментарным гломерулосклерозом (клиническое наблюдение)
Приходина Л.С., Столяревич Е.С., Повилайтите П.Э. LMX1B-ассоциированный стероид-резистентный нефротический синдром c фокально-сегментарным гломерулосклерозом (клиническое наблюдение). Педиатрия. Consilium Medicum. 2025;1:38–43. DOI: 10.26442/26586630.2025.1.203093
© ООО «КОНСИЛИУМ МЕДИКУМ», 2025 г.
© ООО «КОНСИЛИУМ МЕДИКУМ», 2025 г.
________________________________________________
Prikhodina LS, Stolyarevich ES, Povilaitite PE. LMX1B-associated steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis (case report). Pediatrics. Consilium Medicum. 2025;1:38–43. DOI: 10.26442/26586630.2025.1.203093
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Аннотация
Патогенные варианты в гене LMX1B вызывают синдром ногтей-надколенника (nail-patella), характеризующийся дисплазией надколенников, ногтей и локтей, а также поражением почек с развитием фокально-сегментарного гломерулосклероза со специфическими ультраструктурными поражениями гломерулярной базальной мембраны. Представлено клиническое наблюдение за девочкой с LMX1B-ассоциированным стероид-резистентным нефротическим синдромом (СРНС) без характерных для синдрома ногтей-надколенника экстраренальных проявлений со специфическими ультраструктурными изменениями гломерулярной базальной мембраны. Представленное клиническое наблюдение подчеркивает необходимость исключения протеинурии у членов семьи с ребенком со СРНС, а также проведения молекулярно-генетического исследования у всех детей со СРНС до назначения иммуносупрессивной терапии с включением гена LMX1B даже при изолированной патологии почек.
Ключевые слова: стероид-резистентный нефротический синдром, фокально-сегментарный гломерулосклероз, ген LMX1B, синдром ногтей-надколенника
Ключевые слова: стероид-резистентный нефротический синдром, фокально-сегментарный гломерулосклероз, ген LMX1B, синдром ногтей-надколенника
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Pathogenic variants in the LMX1B gene cause nail-patella syndrome, characterized by dysplasia of the patella, nails and elbows, and renal damage with focal segmental glomerulosclerosis (FSGS) with specific ultrastructural lesions of the glomerular basal membrane (GBM). We present a clinical observation of a girl with LMX1B-associated steroid-resistant nephrotic syndrome without the extrarenal characteristic of nail-patella syndrome with specific ultrastructural changes of the GBM. The presented clinical observation emphasizes the necessity to exclude proteinuria in family members with a child with FSGS and to perform molecular genetic study in all children with FSGS before prescribing immunosuppressive therapy with inclusion of LMX1B gene even in case of isolated kidney pathology.
Keywords: steroid-resistant nephrotic syndrome, focal segmental glomerulosclerosis, LMX1B gene, nail-patella syndrome
Полный текст
Список литературы
1. Beals RK, Eckhardt AL. Hereditary onycho-osteodysplasia (Nail-Patella syndrome). A report of nine kindreds. J Bone Joint Surg Am. 1969;51:505-16.
2. Bongers EM, Gubler MC, Knoers NV. Nail-patella syndrome. Overview on clinical and molecular findings. Pediatr Nephrol. 2002;17:703-12.
3. Sweeney E, Fryer A, Mountford R, et al. Nail patella syndrome: a review of the phenotype aided by developmental biology. J Med Genet. 2003;40:153-62.
4. McIntosh I, Dunston JA, Liu L, et al. Nail patella syndrome revisited: 50 years after linkage. Ann Hum Genet. 2005;69:349-63.
5. Lemley KV. Kidney disease in nail-patella syndrome. Pediatr Nephrol. 2009;24:2345-54.
6. Chen H, Lun Y, Ovchinnikov D, et al. Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nat Genet. 1998;19:51-5.
7. Dreyer SD, Zhou G, Baldini A, et al. Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet. 1998;19:47-50.
8. Vollrath D, Jaramillo-Babb VL, Clough MV, et al. Loss-of-function mutations in the LIM-homeodomain gene, LMX1B, in nail-patella syndrome. Hum Mol Genet. 1998;7:1091-8.
9. Ghoumid J, Petit F, Holder-Espinasse M, et al. Nail-patella syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity. Eur J Hum Genet. 2016;24:44-50. DOI:10.1038/ejhg.2015.77
10. Tigchelaar S, Lenting A, Bongers EM, van Kampen A. Nail patella syndrome: knee symptoms and surgical outcomes. A questionnaire-based survey. Orthop Traumatol Surg Res. 2015;101(8):959-62.
11. Sabir AH, Dermanis AA, Irving M, Cheung M. Arthrogryposis as a presenting feature of nail-patella syndrome: a lesser-known feature and the perils of negative whole-genome sequencing. Clin Dysmorphol. 2020;29:177-81.
12. Proesmans W, Van Dyck M, Devriendt K. Nail-patella syndrome, infantile nephrotic syndrome: complete remission with antiproteinuric treatment. Nephrol Dial Transplant. 2009;24:1335-8.
13. Harita Y, Urae S, Akashio R, et al. Clinical and genetic characterization of nephropathy in patients with nail-patella syndrome. Eur J Hum Genet. 2020;28:1414-21.
14. Price A, Cervantes J, Lindsey S, et al. Nail-patella syndrome: clinical clues for making the diagnosis. Cutis. 2018;101:126-9.
15. Chen H. Nail-Patella Syndrome. In: Atlas of Genetic Diagnosis and Counseling. Springer, New York, NY. 2017. DOI:10.1007/978-1-4939-2401-1_172
16. Nakata T, Ishida R, Mihara Y, et al. Steroid-resistant nephrotic syndrome as the initial presentation of nail-patella syndrome: a case of a de novo LMX1B mutation. BMC Nephrol. 2017;18:1-5. DOI:10.1186/s12882-017-0516-7
17. Boyer O, Woerner S, Yang F, et al. LMX1B mutations cause hereditary FSGS without extrarenal involvement. J Am Soc Nephrol. 2013;24(8):1216-22. DOI:10.1681/ASN.2013020171
18. Isojima T, Harita Y, Furuyama M, et al. LMX1B mutation with residual transcriptional activity as a cause of isolated glomerulopathy. Nephrol Dial Transplant. 2014;29(1):81-8. DOI:10.1093/ ndt/gft359.
19. Zuppan CW, Weeks DA, Cutler D. Nail-patella glomerulopathy without associated constitutional abnormalities. Ultrastruct Pathol. 2003;27:357-61.
20. Konomoto T, Imamura H, Orita M, et al. Clinical and histological findings of autosomal dominant renal-limited disease with LMX1B mutation. Nephrology. 2016;21:765-73. DOI:10.1111/nep.12666
21. Edwards N, Rice SJ, Raman S, et al. A novel LMX1B mutation in a family with endstage renal disease of ‘unknown cause’. Clin Kidney J. 2015;8:113-9.
22. Bongers EM, de Wijs IJ, Marcelis C, et al. Identification of entire LMX1B gene deletions in nail patella syndrome: evidence for haploinsufficiency as the main pathogenicmechanism underlying dominant inheritance in man. Eur J Hum Genet. 2008;16:1240-4.
23. Witzgall R. Nail-patella syndrome. Pflugers Arch. 2017;469:927-36.
24. Banno Y, Ikemiyagi M, Hamada R. et al. Nail-patella syndrome with nephropathy in a de novo LMX1B mutation: triangular lunula of the thumb and lack of finger creases as clues. Pediatric Nephrol. 2024;39:2627-31. DOI:10.1007/s00467-024-06344-2
25. Trautmann A, Vivarell M, Samue S, et al. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatr Nephrol. 2020;35:1529-61.
26. Malakasioti G, Iancu D, Milovanova A, et al. A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants. Kidney Int. 2023;103:5:962-72.
27. Bongers EM, Huysmans FT, Levtchenko E, et al. Genotype phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy. Eur J Hum Genet. 2005;13:935-46.
28. Harita Y, Kitanaka S, Isojima T, et al. Spectrum of LMX1B mutations: from nail– patella syndrome to isolated nephropathy. Pediatr Nephrol. 2017;32(10):1845-50. DOI:10.1007/s00467-016-3462-x
2. Bongers EM, Gubler MC, Knoers NV. Nail-patella syndrome. Overview on clinical and molecular findings. Pediatr Nephrol. 2002;17:703-12.
3. Sweeney E, Fryer A, Mountford R, et al. Nail patella syndrome: a review of the phenotype aided by developmental biology. J Med Genet. 2003;40:153-62.
4. McIntosh I, Dunston JA, Liu L, et al. Nail patella syndrome revisited: 50 years after linkage. Ann Hum Genet. 2005;69:349-63.
5. Lemley KV. Kidney disease in nail-patella syndrome. Pediatr Nephrol. 2009;24:2345-54.
6. Chen H, Lun Y, Ovchinnikov D, et al. Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nat Genet. 1998;19:51-5.
7. Dreyer SD, Zhou G, Baldini A, et al. Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet. 1998;19:47-50.
8. Vollrath D, Jaramillo-Babb VL, Clough MV, et al. Loss-of-function mutations in the LIM-homeodomain gene, LMX1B, in nail-patella syndrome. Hum Mol Genet. 1998;7:1091-8.
9. Ghoumid J, Petit F, Holder-Espinasse M, et al. Nail-patella syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity. Eur J Hum Genet. 2016;24:44-50. DOI:10.1038/ejhg.2015.77
10. Tigchelaar S, Lenting A, Bongers EM, van Kampen A. Nail patella syndrome: knee symptoms and surgical outcomes. A questionnaire-based survey. Orthop Traumatol Surg Res. 2015;101(8):959-62.
11. Sabir AH, Dermanis AA, Irving M, Cheung M. Arthrogryposis as a presenting feature of nail-patella syndrome: a lesser-known feature and the perils of negative whole-genome sequencing. Clin Dysmorphol. 2020;29:177-81.
12. Proesmans W, Van Dyck M, Devriendt K. Nail-patella syndrome, infantile nephrotic syndrome: complete remission with antiproteinuric treatment. Nephrol Dial Transplant. 2009;24:1335-8.
13. Harita Y, Urae S, Akashio R, et al. Clinical and genetic characterization of nephropathy in patients with nail-patella syndrome. Eur J Hum Genet. 2020;28:1414-21.
14. Price A, Cervantes J, Lindsey S, et al. Nail-patella syndrome: clinical clues for making the diagnosis. Cutis. 2018;101:126-9.
15. Chen H. Nail-Patella Syndrome. In: Atlas of Genetic Diagnosis and Counseling. Springer, New York, NY. 2017. DOI:10.1007/978-1-4939-2401-1_172
16. Nakata T, Ishida R, Mihara Y, et al. Steroid-resistant nephrotic syndrome as the initial presentation of nail-patella syndrome: a case of a de novo LMX1B mutation. BMC Nephrol. 2017;18:1-5. DOI:10.1186/s12882-017-0516-7
17. Boyer O, Woerner S, Yang F, et al. LMX1B mutations cause hereditary FSGS without extrarenal involvement. J Am Soc Nephrol. 2013;24(8):1216-22. DOI:10.1681/ASN.2013020171
18. Isojima T, Harita Y, Furuyama M, et al. LMX1B mutation with residual transcriptional activity as a cause of isolated glomerulopathy. Nephrol Dial Transplant. 2014;29(1):81-8. DOI:10.1093/ ndt/gft359.
19. Zuppan CW, Weeks DA, Cutler D. Nail-patella glomerulopathy without associated constitutional abnormalities. Ultrastruct Pathol. 2003;27:357-61.
20. Konomoto T, Imamura H, Orita M, et al. Clinical and histological findings of autosomal dominant renal-limited disease with LMX1B mutation. Nephrology. 2016;21:765-73. DOI:10.1111/nep.12666
21. Edwards N, Rice SJ, Raman S, et al. A novel LMX1B mutation in a family with endstage renal disease of ‘unknown cause’. Clin Kidney J. 2015;8:113-9.
22. Bongers EM, de Wijs IJ, Marcelis C, et al. Identification of entire LMX1B gene deletions in nail patella syndrome: evidence for haploinsufficiency as the main pathogenicmechanism underlying dominant inheritance in man. Eur J Hum Genet. 2008;16:1240-4.
23. Witzgall R. Nail-patella syndrome. Pflugers Arch. 2017;469:927-36.
24. Banno Y, Ikemiyagi M, Hamada R. et al. Nail-patella syndrome with nephropathy in a de novo LMX1B mutation: triangular lunula of the thumb and lack of finger creases as clues. Pediatric Nephrol. 2024;39:2627-31. DOI:10.1007/s00467-024-06344-2
25. Trautmann A, Vivarell M, Samue S, et al. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatr Nephrol. 2020;35:1529-61.
26. Malakasioti G, Iancu D, Milovanova A, et al. A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants. Kidney Int. 2023;103:5:962-72.
27. Bongers EM, Huysmans FT, Levtchenko E, et al. Genotype phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy. Eur J Hum Genet. 2005;13:935-46.
28. Harita Y, Kitanaka S, Isojima T, et al. Spectrum of LMX1B mutations: from nail– patella syndrome to isolated nephropathy. Pediatr Nephrol. 2017;32(10):1845-50. DOI:10.1007/s00467-016-3462-x
________________________________________________
1. Beals RK, Eckhardt AL. Hereditary onycho-osteodysplasia (Nail-Patella syndrome). A report of nine kindreds. J Bone Joint Surg Am. 1969;51:505-16.
2. Bongers EM, Gubler MC, Knoers NV. Nail-patella syndrome. Overview on clinical and molecular findings. Pediatr Nephrol. 2002;17:703-12.
3. Sweeney E, Fryer A, Mountford R, et al. Nail patella syndrome: a review of the phenotype aided by developmental biology. J Med Genet. 2003;40:153-62.
4. McIntosh I, Dunston JA, Liu L, et al. Nail patella syndrome revisited: 50 years after linkage. Ann Hum Genet. 2005;69:349-63.
5. Lemley KV. Kidney disease in nail-patella syndrome. Pediatr Nephrol. 2009;24:2345-54.
6. Chen H, Lun Y, Ovchinnikov D, et al. Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nat Genet. 1998;19:51-5.
7. Dreyer SD, Zhou G, Baldini A, et al. Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet. 1998;19:47-50.
8. Vollrath D, Jaramillo-Babb VL, Clough MV, et al. Loss-of-function mutations in the LIM-homeodomain gene, LMX1B, in nail-patella syndrome. Hum Mol Genet. 1998;7:1091-8.
9. Ghoumid J, Petit F, Holder-Espinasse M, et al. Nail-patella syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity. Eur J Hum Genet. 2016;24:44-50. DOI:10.1038/ejhg.2015.77
10. Tigchelaar S, Lenting A, Bongers EM, van Kampen A. Nail patella syndrome: knee symptoms and surgical outcomes. A questionnaire-based survey. Orthop Traumatol Surg Res. 2015;101(8):959-62.
11. Sabir AH, Dermanis AA, Irving M, Cheung M. Arthrogryposis as a presenting feature of nail-patella syndrome: a lesser-known feature and the perils of negative whole-genome sequencing. Clin Dysmorphol. 2020;29:177-81.
12. Proesmans W, Van Dyck M, Devriendt K. Nail-patella syndrome, infantile nephrotic syndrome: complete remission with antiproteinuric treatment. Nephrol Dial Transplant. 2009;24:1335-8.
13. Harita Y, Urae S, Akashio R, et al. Clinical and genetic characterization of nephropathy in patients with nail-patella syndrome. Eur J Hum Genet. 2020;28:1414-21.
14. Price A, Cervantes J, Lindsey S, et al. Nail-patella syndrome: clinical clues for making the diagnosis. Cutis. 2018;101:126-9.
15. Chen H. Nail-Patella Syndrome. In: Atlas of Genetic Diagnosis and Counseling. Springer, New York, NY. 2017. DOI:10.1007/978-1-4939-2401-1_172
16. Nakata T, Ishida R, Mihara Y, et al. Steroid-resistant nephrotic syndrome as the initial presentation of nail-patella syndrome: a case of a de novo LMX1B mutation. BMC Nephrol. 2017;18:1-5. DOI:10.1186/s12882-017-0516-7
17. Boyer O, Woerner S, Yang F, et al. LMX1B mutations cause hereditary FSGS without extrarenal involvement. J Am Soc Nephrol. 2013;24(8):1216-22. DOI:10.1681/ASN.2013020171
18. Isojima T, Harita Y, Furuyama M, et al. LMX1B mutation with residual transcriptional activity as a cause of isolated glomerulopathy. Nephrol Dial Transplant. 2014;29(1):81-8. DOI:10.1093/ ndt/gft359.
19. Zuppan CW, Weeks DA, Cutler D. Nail-patella glomerulopathy without associated constitutional abnormalities. Ultrastruct Pathol. 2003;27:357-61.
20. Konomoto T, Imamura H, Orita M, et al. Clinical and histological findings of autosomal dominant renal-limited disease with LMX1B mutation. Nephrology. 2016;21:765-73. DOI:10.1111/nep.12666
21. Edwards N, Rice SJ, Raman S, et al. A novel LMX1B mutation in a family with endstage renal disease of ‘unknown cause’. Clin Kidney J. 2015;8:113-9.
22. Bongers EM, de Wijs IJ, Marcelis C, et al. Identification of entire LMX1B gene deletions in nail patella syndrome: evidence for haploinsufficiency as the main pathogenicmechanism underlying dominant inheritance in man. Eur J Hum Genet. 2008;16:1240-4.
23. Witzgall R. Nail-patella syndrome. Pflugers Arch. 2017;469:927-36.
24. Banno Y, Ikemiyagi M, Hamada R. et al. Nail-patella syndrome with nephropathy in a de novo LMX1B mutation: triangular lunula of the thumb and lack of finger creases as clues. Pediatric Nephrol. 2024;39:2627-31. DOI:10.1007/s00467-024-06344-2
25. Trautmann A, Vivarell M, Samue S, et al. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatr Nephrol. 2020;35:1529-61.
26. Malakasioti G, Iancu D, Milovanova A, et al. A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants. Kidney Int. 2023;103:5:962-72.
27. Bongers EM, Huysmans FT, Levtchenko E, et al. Genotype phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy. Eur J Hum Genet. 2005;13:935-46.
28. Harita Y, Kitanaka S, Isojima T, et al. Spectrum of LMX1B mutations: from nail– patella syndrome to isolated nephropathy. Pediatr Nephrol. 2017;32(10):1845-50. DOI:10.1007/s00467-016-3462-x
Авторы
Л.С. Приходина*1,2, Е.С. Столяревич3,4, П.Э. Повилайтите5
1Научно-исследовательский клинический институт педиатрии и детской хирургии им. акад. Ю.Е. Вельтищева – ОСП ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России (Пироговский Университет), Москва, Россия;
2ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия;
3ФГБОУ ВО «Российский университет медицины» Минздрава России, Москва, Россия;
4ГБУЗ «Городская клиническая больница №52» Департамента здравоохранения г. Москвы, Москва, Россия;
5ГБУ РО «Патолого-анатомическое бюро», Ростов-на-Дону, Россия
*Prikhodina@rambler.ru
1Научно-исследовательский клинический институт педиатрии и детской хирургии им. акад. Ю.Е. Вельтищева – ОСП ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России (Пироговский Университет), Москва, Россия;
2ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия;
3ФГБОУ ВО «Российский университет медицины» Минздрава России, Москва, Россия;
4ГБУЗ «Городская клиническая больница №52» Департамента здравоохранения г. Москвы, Москва, Россия;
5ГБУ РО «Патолого-анатомическое бюро», Ростов-на-Дону, Россия
*Prikhodina@rambler.ru
________________________________________________
Larisa S. Prikhodina*1,2, Ekaterina S. Stolyarevich3,4, Patricia E. Povilaitite5
1Veltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery of the Pirogov Russian National Research Medical University (Pirogov University), Moscow, Russia;
2Russian Medical Academy of Continuous Professional Education, Moscow, Russia;
3Russian University of Medicine, Moscow, Russia;
4City Clinical Hospital №52, Moscow, Russia;
5Pathological and Anatomical Bureau, Rostov-on-Don, Russia
*Prikhodina@rambler.ru
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