rospedjРоссийский педиатрический журналRussian Pediatric Journal2687-0843Издательство «ПедиатрЪ»10.15690/rpj.v2i1.2191rospedj-94Research ArticleКЛИНИЧЕСКИЕ НАБЛЮДЕНИЯКлинико-генетические характеристики метафизарной хондродисплазии МакКьюсика (гипоплазии хряща и волос), обусловленной мутациями в гене RMRP, в детском возрасте: собственные наблюдения и обзор литературыClinical genetic characteristics of metaphyseal chondrodysplasia, McKusick type (cartilage-hair hypoplasia) in children caused by mutations in the RMRP gene: authors’ observations and literature reviewhttps://orcid.org/0000-0002-2672-6294МарковаТ. В.MarkovaT. V.

Москва

Tatiana V. Markova

Moscow

https://orcid.org/0000-0002-7651-8485КенисВ. М.KenisV. M.

Кенис Владимир Маркович, доктор медицинских наук, врач травматолог-ортопед Консультативно-диагностического центра на Лахтинской улице

197136, Санкт-Петербург, ул. Лахтинская, д. 12, лит. А

Vladimir M. Kenis

Saint-Petersburg

kenis@mail.ruhttps://orcid.org/0000-0002-2883-4029СуминаМ. Г.SuminaM. G.

Екатеринбург

Maria G. Sumina

Yekaterinburg

https://orcid.org/0000-0003-4905-1303ЩагинаО. А.ShchaginaO. A.

Москва

Olga A. Shchagina

Moscow

https://orcid.org/0000-0003-4527-4518НагорноваТ. С.NagornovaT. S.

Москва

Tatiana S. Nagornova

Moscow

https://orcid.org/0000-0003-1139-5573МельченкоЕ. В.MelchenkoE. V.

Санкт-Петербург

Evgenii V. Melchenko

Saint-Petersburg

https://orcid.org/0000-0001-7535-2797НиколаеваЕ. Б.NikolaevaE. B.

Екатеринбург

Elena B. Nikolaeva

Yekaterinburg

https://orcid.org/0000-0001-5602-2805ДадалиЕ. Л.DadaliE. L.

Москва

Elena L. Dadali

Moscow

Медико-генетический научный центр имени академика Н.П. Бочкова Министерства образования науки РоссииРоссияN. P. Bochkov Research Center for Medical Genetics, Ministry of Education and Science of the Russian FederationRussian FederationНациональный медицинский исследовательский центр детской травматологии и ортопедии имени Г.И. Турнера Министерства здравоохранения РоссииРоссияH. Turner National Medical Research Center for Сhildren's Orthopedics and Trauma Surgery, Ministry of Health of the Russian FederationRussian FederationКлинико-диагностический центр «Охрана здоровья матери и ребенка»РоссияClinical Diagnostic Center “Mother and Child Healthcare”Russian Federation20212805202121512Copyright © Маркова Т.В., Кенис В.М., Сумина М.Г., Щагина О.А., Нагорнова Т.С., Мельченко Е.В., Николаева Е.Б., Дадали Е.Л., 20212021Маркова Т.В., Кенис В.М., Сумина М.Г., Щагина О.А., Нагорнова Т.С., Мельченко Е.В., Николаева Е.Б., Дадали Е.Л.Markova T.V., Kenis V.M., Sumina M.G., Shchagina O.A., Nagornova T.S., Melchenko E.V., Nikolaeva E.B., Dadali E.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.rospedj.ru/jour/article/view/94Введение

Введение. Метафизарная хондродисплазия Мак-Кьюсика (МХДМ) (OMIM: #250250) (гипоплазия хряща и волос) — редкое аутосомно-рецессивное заболевание, основными клиническими проявлениями которого являются непропорциональный нанизм, истончение волос и гипотрихоз. У части пациентов отмечается клеточный и гуморальный иммунодефицит, бронхоэктазы и болезнь Гиршпрунга. Больные имеют повышенный риск возникновения злокачественных новообразований и гипопластической анемии. МХДМ — одно из редких моногенных заболеваний, обусловленных мутациями в гене RMRP, кодирующем не белок, а нетранслируемую РНК. К настоящему времени описано 123 патогенных варианта. Обнаружение клинико-генетических корреляций у больных с различными типами и локализацией мутаций в гене будет способствовать совершенствованию представлений о патогенетических механизмах заболевания и позволит прогнозировать спектр и тяжесть клинических симптомов у отдельных больных.

Материалы и методы исследования. Нами представлено первое описание клинико-генетических характеристик двух российских больных с МХДМ, обусловленной мутациями в гене RMRP, и проведено их сопоставление с литературными данными. Диагноз в обоих случаях был подтвержден при анализе гена RMRP методом прямого автоматического секвенирования по Сенгеру.

Результаты

Результаты. Анализ особенностей клинических проявлений наблюдаемых нами больных и пациентов, описанных в литературе, показал наличие типичных скелетных и внескелетных проявлений, позволяющих заподозрить наличие МХДМ при клиническом осмотре. У наблюдаемых нами российских больных обнаружена мажорная мутация в популяциях амишей и финнов, n.71A>G, в компаунд-гетерозиготном состоянии с двумя другими: у одного больного с ранее описанной мутацией n.80G>A, а у другого — с вновь выявленной мутацией n.76C>T. Все обнаруженные мутации были локализованы в высококонсервативной области первого домена, которому принадлежит основная роль в функционировании эндорибонуклеазного комплекса.

Выводы

Выводы. Учитывая малые размеры гена и наличие специфических признаков МХДМ, самым точным и дешевым способом молекулярно-генетической диагностики является определение мутаций в гене RMRP методом прямого автоматического секвенирования по Сенгеру. Своевременная диагностика МХДМ позволяет выбрать правильную тактику наблюдения пациентов с данной патологией. 

Introduction

Introduction. Metaphyseal chondrodysplasia, McKusick type (MCD) (OMIM: #250250) (cartilage-hair hypoplasia) is a rare, autosomal recessive disorder with main clinical manifestations including disproportionate short stature, hair thinning and hypotrichosis. Some patients with MCD develop cellular and humoral immunodeficiency, bronchiectases and Hirschsprung disease. Such patients have an increased risk of developing malignant tumors and hypoplastic anemia. MCD is one of the rare monogenic disorders caused by mutations in the RMRP gene encoding a non-coding RNA instead of a protein. So far, 123 pathogenic RMRP variants have been described. The evidence of clinical genetic correlations in patients with different types and localization of gene mutations will facilitate further understanding of pathogenetic mechanisms of the disorder and enable to predict the spectrum and severity of clinical symptoms in individual patients.

Materials and methods

Materials and methods. We present the first description of clinical genetic characteristics of two Russian patients with MCD caused by mutations in the RMRP gene, along with the comparison of our results with literature data. In both cases the diagnosis was confirmed by analyzing the RMRP gene sequence using the direct Sanger sequencing technique.

Results

Results. Analysis of specific clinical signs observed during clinical examination of our patients in comparison with those reported in literature has shown the presence of typical skeletal and extraskeletal manifestations suggestive of MCD. In Russian patients we found the major mutation previously described in the Amish and Finnish populations, n.71A>G, present in compound heterozygous state, along with two other mutations: in one patient with an earlier described n.80G>A mutation, and in the other — a newly detected n.76C>T mutation. All detected mutations were mapped to a highly conserved region of the first domain that plays a major role in the functioning of the endoribonuclease complex.

Conclusions

Conclusions. Considering the small size of the RMRP gene and presence of specific signs of MCD, the most accurate and inexpensive method of molecular genetic analysis is the detection of mutations in the RMRP gene using direct automated Sanger sequencing. Timely diagnosis of MCD enables to choose the correct follow-up strategy for patients with this disorder.

метафизарная хондродисплазия Мак-Кьюсикагипоплазия хряща и волосболезнь Гиршпрунгаген RMRPмутацииMcKusick type metaphyseal chondrodysplasiacartilage-hair hypoplasiaHirschsprung diseaseRMRP genemutationsReferencesMcKusick VA, Eldridge R, Hostetler JA, et al. Dwarfism in the Amish. II. Cartilage-hair hypoplasia. Bull Johns Hopkins Hosp. 1965;116:285–326.McKusick VA, Eldridge R, Hostetler JA, et al. Dwarfism in the Amish. II. Cartilage-hair hypoplasia. Bull Johns Hopkins Hosp. 1965;116:285–326.Mäkitie O, Kaitila I. Cartilage-hair hypoplasia-clinical manifestations in 108 Finnish patients. Eur J Pediatr. 1993;152(3):211–217. doi: 10.1007/BF01956147Mäkitie O, Kaitila I. Cartilage-hair hypoplasia-clinical manifestations in 108 Finnish patients. Eur J Pediatr. 1993;152(3):211–217. doi: 10.1007/BF01956147Ridanpää M, van Eenennaam H, Pelin K, et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell. 2001;104(2):195–203. doi: 10.1016/s0092-8674(01)00205-7Ridanpää M, van Eenennaam H, Pelin K, et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell. 2001;104(2):195–203. doi: 10.1016/s0092-8674(01)00205-7Mäkitie O, Rajantie J, Kaitila I. Anaemia and macrocytosis — unrecognized features in cartilage-hair hypoplasia. Acta Paediatr. 1992;81(12):1026–9. doi: 10.1111/j.1651-2227.1992.tb12168.xMäkitie O, Rajantie J, Kaitila I. Anaemia and macrocytosis — unrecognized features in cartilage-hair hypoplasia. Acta Paediatr. 1992;81(12):1026–9. doi: 10.1111/j.1651-2227.1992.tb12168.xWilliams MS, Ettinger RS, Hermanns P, et al. The natural history of severe anemia in cartilage-hair hypoplasia. Am J Med Genet A. 2005;138(1):35–40. doi: 10.1002/ajmg.a.30902Williams MS, Ettinger RS, Hermanns P, et al. The natural history of severe anemia in cartilage-hair hypoplasia. Am J Med Genet A. 2005;138(1):35–40. doi: 10.1002/ajmg.a.30902Mäkitie O, Pukkala E, Teppo L, Kaitila I. Increased incidence of cancer in patients with cartilage-hair hypoplasia. J Pediatr. 1999;134(3):315–318. doi: 10.1016/s0022-3476(99)70456-7Mäkitie O, Pukkala E, Teppo L, Kaitila I. Increased incidence of cancer in patients with cartilage-hair hypoplasia. J Pediatr. 1999;134(3):315–318. doi: 10.1016/s0022-3476(99)70456-7Taskinen M, Ranki A, Pukkala E, et al. Extended follow-up of the Finnish cartilage-hair hypoplasia cohort confirms high incidence of non-Hodgkin lymphoma and basal cell carcinoma. Am J Med Genet A. 2008;146A(18):2370–2375. doi: 10.1002/ajmg.a.32478Taskinen M, Ranki A, Pukkala E, et al. Extended follow-up of the Finnish cartilage-hair hypoplasia cohort confirms high incidence of non-Hodgkin lymphoma and basal cell carcinoma. Am J Med Genet A. 2008;146A(18):2370–2375. doi: 10.1002/ajmg.a.32478Kaitila I, Perheentupa J. Cartilage-hair hypoplasia (CHH). In: Eriksson AW, Forsius HR, Nevanlinna HR, eds. Population Structure and Genetic Disorders. New York: Academic Press (pub.); 1980. pp. 588–591.Kaitila I, Perheentupa J. Cartilage-hair hypoplasia (CHH). In: Eriksson AW, Forsius HR, Nevanlinna HR, eds. Population Structure and Genetic Disorders. New York: Academic Press (pub.); 1980. pp. 588–591.Mäkitie O. Cartilage-hair hypoplasia in Finland: epidemiological and genetic aspects of 107 patients. J Med Genet. 1992;29(9):652– 655. doi: 10.1136/jmg.29.9.652Mäkitie O. Cartilage-hair hypoplasia in Finland: epidemiological and genetic aspects of 107 patients. J Med Genet. 1992;29(9):652– 655. doi: 10.1136/jmg.29.9.652Hsieh C-L, Donlon TA, Darras BT, et al. The gene for the RNA component of the mitochondrial RNA-processing endoribonuclease is located on human chromosome 9p and on mouse chromosome 4. Genomics. 1990; 6(3):540–544. doi: 10.1016/0888-7543(90)90483-bHsieh C-L, Donlon TA, Darras BT, et al. The gene for the RNA component of the mitochondrial RNA-processing endoribonuclease is located on human chromosome 9p and on mouse chromosome 4. Genomics. 1990; 6(3):540–544. doi: 10.1016/0888-7543(90)90483-bClayton DA. A big development for a small RNA. Nature. 2001;410(6824):29–31. doi: 10.1038/35065191Clayton DA. A big development for a small RNA. Nature. 2001;410(6824):29–31. doi: 10.1038/35065191Bonafe L, Schmitt K, Eich G, et al. RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms. Clin Genet. 2002;61(2):146–151. doi: 10.1034/j.1399-0004.2002.610210.xBonafe L, Schmitt K, Eich G, et al. RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms. Clin Genet. 2002;61(2):146–151. doi: 10.1034/j.1399-0004.2002.610210.xHorn D, Rupprecht E, Kunze J, Spranger J. Anauxetic dysplasia, a spondylometaepiphyseal dysplasia with extreme dwarfism. J Med Genet. 2001;38(4):262–5. doi: 10.1136/jmg.38.4.262Horn D, Rupprecht E, Kunze J, Spranger J. Anauxetic dysplasia, a spondylometaepiphyseal dysplasia with extreme dwarfism. J Med Genet. 2001;38(4):262–5. doi: 10.1136/jmg.38.4.262Mäkitie O, Vakkilainen S, Thiel CT. Cartilage-Hair Hypoplasia — Anauxetic Dysplasia Spectrum Disorders. March 15, 2012; Last Update: August 6, 2020. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–2020. Available online: https://www.ncbi.nlm.nih.gov/books/NBK84550. Accessed on April 5, 2021.Mäkitie O, Vakkilainen S, Thiel CT. Cartilage-Hair Hypoplasia — Anauxetic Dysplasia Spectrum Disorders. March 15, 2012; Last Update: August 6, 2020. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–2020. Available online: https://www.ncbi.nlm.nih.gov/books/NBK84550. Accessed on April 5, 2021.Ridanpää M, Sistonen P, Rockas S, et al. Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major 70A-G mutation of the untranslated RMRP. Eur J Hum Genet. 2002;10(7):439–447. doi: 10.1038/sj.ejhg.5200824Ridanpää M, Sistonen P, Rockas S, et al. Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major 70A-G mutation of the untranslated RMRP. Eur J Hum Genet. 2002;10(7):439–447. doi: 10.1038/sj.ejhg.5200824Ridanpää M, Jain P, McKusick VA, et al. The major mutation in the RMRP gene causing CHH among the Amish is the same as that found in most Finnish cases. Am J Med Genet C Semin Med Genet. 2003;121C(1):81–83. doi: 10.1002/ajmg.c.20006Ridanpää M, Jain P, McKusick VA, et al. The major mutation in the RMRP gene causing CHH among the Amish is the same as that found in most Finnish cases. Am J Med Genet C Semin Med Genet. 2003;121C(1):81–83. doi: 10.1002/ajmg.c.20006Nakashima E, Mabuchi A, Kashimada K, et al. RMRP mutations in Japanese patients with cartilage-hair hypoplasia. Am J Med Genet A. 2003;123A(3):253–256. doi: 10.1002/ajmg.a.20281Nakashima E, Mabuchi A, Kashimada K, et al. RMRP mutations in Japanese patients with cartilage-hair hypoplasia. Am J Med Genet A. 2003;123A(3):253–256. doi: 10.1002/ajmg.a.20281Gomes ME, Calatrava Paternostro L, Moura VR, et al. Identification of Novel and Recurrent RMRP Variants in a Series of Brazilian Patients with Cartilage-Hair Hypoplasia: McKusick Syndrome. Mol Syndromol. 2020;10(5):255–263. doi: 10.1159/000501892Gomes ME, Calatrava Paternostro L, Moura VR, et al. Identification of Novel and Recurrent RMRP Variants in a Series of Brazilian Patients with Cartilage-Hair Hypoplasia: McKusick Syndrome. Mol Syndromol. 2020;10(5):255–263. doi: 10.1159/000501892Steinbusch MMF, Caron MMJ, Surtel DAM, et al. Expression of RMRP RNA is regulated in chondrocyte hypertrophy and determines chondrogenic differentiation. Sci Rep. 2017;7(1):6440. doi: 10.1038/s41598-017-06809-5Steinbusch MMF, Caron MMJ, Surtel DAM, et al. Expression of RMRP RNA is regulated in chondrocyte hypertrophy and determines chondrogenic differentiation. Sci Rep. 2017;7(1):6440. doi: 10.1038/s41598-017-06809-5Mäkitie O, Sulisalo T, de la Chapelle A, Kaitila I. Cartilage-hair hypoplasia. J Med Genet. 1995;32(1):39–43. doi: 10.1136/jmg.32.1.39Mäkitie O, Sulisalo T, de la Chapelle A, Kaitila I. Cartilage-hair hypoplasia. J Med Genet. 1995;32(1):39–43. doi: 10.1136/jmg.32.1.39Coupe RL, Lowry RB. Abnormality of the hair in cartilagehair hypoplasia. Dermatologica. 1970;141(1):329–334. doi: 10.1159/000252497Coupe RL, Lowry RB. Abnormality of the hair in cartilagehair hypoplasia. Dermatologica. 1970;141(1):329–334. doi: 10.1159/000252497Narayanan DL, Shukla A, Siddesh AR, et al. Cartilage hair hypoplasia: two unrelated cases with g.70 A > G mutation in RMRP gene. Indian J Pediatr. 2016;83(9):1003–1005. doi: 10.1007/s12098-015-1947-4Narayanan DL, Shukla A, Siddesh AR, et al. Cartilage hair hypoplasia: two unrelated cases with g.70 A > G mutation in RMRP gene. Indian J Pediatr. 2016;83(9):1003–1005. doi: 10.1007/s12098-015-1947-4Kostjukovits S, Klemetti P, Föhr A, et al. High prevalence of bronchiectasis in patients with cartilage-hair hypoplasia. J Allergy Clin Immunol. 2017;139(1):375–378. doi: 10.1016/j.jaci.2016.07.023Kostjukovits S, Klemetti P, Föhr A, et al. High prevalence of bronchiectasis in patients with cartilage-hair hypoplasia. J Allergy Clin Immunol. 2017;139(1):375–378. doi: 10.1016/j.jaci.2016.07.023Rider NL, Morton DH, Puffenberger E, et al. Immunologic and clinical features of 25 Amish patients with RMRP 70 A-->G cartilage hair hypoplasia. Clin Immunol. 2009;131(1):119–128. doi: 10.1016/j.clim.2008.11.001Rider NL, Morton DH, Puffenberger E, et al. Immunologic and clinical features of 25 Amish patients with RMRP 70 A-->G cartilage hair hypoplasia. Clin Immunol. 2009;131(1):119–128. doi: 10.1016/j.clim.2008.11.001Faitelson Y, Manson D. Cartilage-hair hypoplasia: a spectrum of clinical and radiological findings. LymphoSign Journal. 2015;2(3):157–164. doi: 10.14785/lpsn-2015-0009Faitelson Y, Manson D. Cartilage-hair hypoplasia: a spectrum of clinical and radiological findings. LymphoSign Journal. 2015;2(3):157–164. doi: 10.14785/lpsn-2015-0009Klemetti P, Valta H, Kostjukovits S, et al. Cartilage-hair hypoplasia with normal height in childhood-4 patients with a unique genotype. Clin Genet. 2017;92(2):204–207. doi: 10.1111/cge.12969Klemetti P, Valta H, Kostjukovits S, et al. Cartilage-hair hypoplasia with normal height in childhood-4 patients with a unique genotype. Clin Genet. 2017;92(2):204–207. doi: 10.1111/cge.12969Mäkitie O, Heikkinen M, Kaitila I, Rintala R. Hirschsprung's disease in cartilage-hair hypoplasia has poor prognosis. J Pediatr Surg. 2002;37(11):1585–1588. doi: 10.1053/jpsu.2002.36189Mäkitie O, Heikkinen M, Kaitila I, Rintala R. Hirschsprung's disease in cartilage-hair hypoplasia has poor prognosis. J Pediatr Surg. 2002;37(11):1585–1588. doi: 10.1053/jpsu.2002.36189Thiel CT, Mortier G, Kaitila I, et al. Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. Am J Hum Genet. 2007;81(3):519–529. doi: 10.1086/521034Thiel CT, Mortier G, Kaitila I, et al. Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. Am J Hum Genet. 2007;81(3):519–529. doi: 10.1086/521034Vakkilainen S, Costantini A, Taskinen M, et al. Metaphyseal dysplasia without hypotrichosis’ can present with late-onset extraskeletal manifestations. J Med Genet. 2020;57(1):18–22. doi: 10.1136/jmedgenet-2019-106131Vakkilainen S, Costantini A, Taskinen M, et al. Metaphyseal dysplasia without hypotrichosis’ can present with late-onset extraskeletal manifestations. J Med Genet. 2020;57(1):18–22. doi: 10.1136/jmedgenet-2019-106131

The authors declare that there are no conflicts of interest present.