rospedРоссийский педиатрический журнал имени М.Я. СтуденикинаM.Ya. Studenikin Russian Pediatric JournalФГАУ «НМИЦ здоровья детей» Минздрава России10.46563/1560-9561-2023-26-3-159-167xnbjeyrosped-4Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL INVESTIGATIONSКлинико-генетические параллели у сибсов с муковисцидозомGenotype-phenotype correlation in siblings with cystic fibrosisКрасновидоваАнастасия ЕвгеньевнаKrasnovidovaAnatasiya E.

Клинический ординатор, ассистент каф. педиатрии и детской ревматологии ФГАОУ ВО «Первый МГМУ им. И.М. Сеченова» Минздрава России (Сеченовский Университет).

e-mail: dr.krasnovidova@yandex.ru

For correspondence: Anastasiya E. Krasnovidova, assistant of the Department of paediatrics and paediatric rheumatology of the I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russian Federation

e-mail: dr.krasnovidova@yandex.ru

dr.krasnovidova@yandex.ruСимоноваОльга ИгоревнаSimonovaOlga I.

Доктор мед. наук, зав. пульмонологическим отд-нием ФГАУ «НМИЦ здоровья детей» Минздрава России, проф. каф. педиатрии и детской ревматологии ФГАОУ ВО «Первый МГМУ им. И.М. Сеченова» Минздрава России (Сеченовский Университет)

noemail@neicon.ruЧерневичВера ПетровнаChernevichVera P.

Мл. науч. сотр., лаб. редких наследственных болезней у детей ФГАУ «НМИЦ здоровья детей» Минздрава России

noemail@neicon.ruПахомовАлександр ВладимировичPakhomovAleksandr V.

Науч. сотр. лаб. медицинской геномики Медико-генетического центра ФГАУ «НМИЦ здоровья детей» Минздрава России

noemail@neicon.ruРейхАлександра ПавловнаReykhAleksandra P.

Студентка клинического института детского здоровья им. Н.Ф. Филатова ФГАОУ ВО «Первый МГМУ им. И.М. Сеченова» Минздрава России (Сеченовский Университет)

noemail@neicon.ruПушковАлександр АлексеевичPushkovAleksandr A.

Канд. биол. наук, вед. науч. сотр., лаб. медицинской геномики Медико-генетического центра ФГАУ «НМИЦ здоровья детей» Минздрава России

noemail@neicon.ruФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет)I.M. Sechenov First Moscow State Medical University (Sechenov University)ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет); ФГАУ «Национальный медицинский исследовательский центр здоровья детей» Минздрава РоссииI.M. Sechenov First Moscow State Medical University (Sechenov University); National Medical Research Center for Children’s HealthФГАУ «Национальный медицинский исследовательский центр здоровья детей» Минздрава РоссииNational Medical Research Center for Children’s Health202309082023263159167Copyright © Красновидова А.Е., Симонова О.И., Черневич В.П., Пахомов А.В., Рейх А.П., Пушков А.А., 20232023Красновидова А.Е., Симонова О.И., Черневич В.П., Пахомов А.В., Рейх А.П., Пушков А.А.Krasnovidova A.E., Simonova O.I., Chernevich V.P., Pakhomov A.V., Reykh A.P., Pushkov A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.rosped.ru/jour/article/view/4Введение

Введение. Выявляемость муковисцидоза (МВ) более чем у 1 ребёнка в семье не является редкостью. Считается, что одинаковый генотип обусловливает характерный фенотип у больных МВ, особенно у сибсов. Однако широкая клиническая гетерогенность МВ может указывать на воздействие вторичных генетических факторов на течение болезни.

Цель

Цель: определить клинико-генетические параллели и особенности течения МВ у сибсов, в том числе близнецов с МВ из одной семьи.

Материалы и методы

Материалы и методы. В клиническое ретроспективное обсервационное исследование включено 53 сибса (23 мальчика, 30 девочек) в возрасте 6 мес–17 лет 9 мес, средний возраст 8,3 (4,8–12,9) года с разницей в возрасте 5,0 ± 2,3 года с диагнозом МВ. Больные были распределены на 2 группы: 1 группу составили 9 пар близнецов (3 — монозиготные, 6 — дизиготные), 2 группу — 35 полных сибсов.

Результаты

Результаты. Медиана возраста постановки диагноза МВ старшим сибсам — 2,5 года (8 мес–9,8 года), младшим сибсам — 8,5 мес (1,3 мес–3 года). Хронологически дебют МВ зафиксирован раньше у 3 (16,7%) младших, чем у старших сибсов. У 6 (22,2%) семей панкреатический статус сибсов варьировал от нормальной функции до тяжёлой панкреатической недостаточности, при этом развитие панкреатита отмечалось только у 4 (7,6%) пациентов. В 21 (77,8%) семье были дети, инфицированные Pseudomonas aeruginosa, из них в 5 (23,8%) парах сибсов отмечался одновременный первичный высев патогена, в 8 (38,1%) — высев у обоих детей, но с разницей от 1 мес до 9,5 года (Ме = 3,2), высев только у 1 сибса отмечался в 8 (38,1%) семьях. У всех младших сибсов первичное инфицирование отмечалось в более раннем возрасте со средней разницей в 5,3 года (2–6,6 года). В 10 (37,0%) семьях функциональное состояние лёгких у сибсов различалось. Число обострений бронхолёгочного процесса за год было у 8 (29,6%) пар сибсов и в среднем составляло 1,3 ± 0,5 у старших сибсов, 1,1 ± 0,3 — у младших и 1,7 ± 1,3 — у близнецов. Выраженность гепатобилиарного поражения различалась у 9 (33,3%) пар сибсов, отсутствие патологии у 6 (33,3%) пациентов, МВ-ассоциированный фиброз у 7 (38,9%), цирроз с портальной гипертензией — у 5 (27,8%).

Заключение

Заключение. Для сибсов с МВ, несмотря на одинаковый генотип, сходные условия среды и высокий риск перекрёстного инфицирования, характерна широкая клиническая вариабельность, что связано с воздействием вторичных генетических и эпигенетических факторов на течение МВ. Кроме казуальных генетических вариантов в гене CFTR важную роль в модификации фенотипа при МВ играют не только гены-модификаторы, но и малые молекулы микроРНК, а также метилирование ДНК.

Участие авторов

Участие авторов: Красновидова А.Е., Симонова О.И., Черневич В.П. — концепция и дизайн исследования; Красновидова А.Е., Пахомов А.В., Рейх А.П. — сбор и обработка материала; Красновидова А.Е. — статистическая обработка; Красновидова А.Е., Пушков А.А. — написание текста; Красновидова А.Е., Пушков А.А., Симонова О.И. — редактирование. Все соавторы — утверждение окончательного варианта статьи, ответственность за целостность всех частей статьи.

Финансирование

Финансирование. Исследование не имело финансовой поддержки.

Конфликт интересов

Конфликт интересов. Авторы заявляют об отсутствии конфликта интересов. 

Поступила 18

Поступила 18.04.2023Принята к печати 16.05.2023Опубликована 27.06.2023

Introduction

Introduction. Despite the genetic counseling, families with cystic fibrosis (CF) patients and modern possibilities of prenatal molecular genetic screening, the occurrence of CF in more than one child in a family is not rare. The same genotype is expected to determine the specific phenotype in CF patients, especially in siblings. However, broad clinical heterogeneity could indicate the influence of secondary genetic factors on the course of the disease.

The aim of the study is to examine the genotype-phenotype correlation and disease course features in CF siblings, including twins.

Materials and methods

Materials and methods. A clinical retrospective cohort observational study included fifty three sibs (23 boys, 30 girls) aged from 6 months to 17 years 9 months (median age of 8.3 (4.8–12.9) years, age difference 5 ± 2 years) with a diagnosis of CF confirmed by molecular genetic methods. Group 1 consisted of  9 twin pairs (3 — monozygotic, 6 — dizygotic), group 2 — 35 complete sibs.

Results

Results. The mean age of diagnosis for older sibs is 2.5 years (8 months — 9,8 years; min — 1 months, max — 17 years) and for younger sibs — 8.5 months (1.3 months–3 years). Chronologically, the onset of CF was registered earlier in younger sibs than in older sibs in 3 (16.7%). In 6 (22.2%) of families, the pancreatic status of sibs varied from normal function to severe pancreatic insufficiency, with the occurrence of pancreatitis observed in only 4 (7.6%) patients. In 21 (77.8%) families with sibs infected by P.aeruginosa, 5 (23.8%) had a simultaneous primary culture of the pathogen, 8 (38,1%) had culture in both children but with an interval from 1 month to 9.5 years (Ме: 3.2 (5 months–4.9 years), and in 8 (38.1%) had culture in only 1 sibling. All younger sibs had the primary contamination at an earlier age with a 5.3 year (2–6.6 years;) difference. In 10 (37.0%) of the families, the pulmonary function of the sibs was variable. The number of bronchopulmonary exacerbations per year ranged in 8 (29.6%) of sib pairs and averaged 1.3 ± 0.5 in older sibs, 1.1 ± 0.3 in younger sibs, and 1.7 ± 1.3 in twins. The severity of hepatic involvement varied in 9 (33.3%) of sib pairs: no morbidity in 6 (33.3%), cystic fibrosis-associated fibrosis in 7 (38.9%), and cirrhosis with portal hypertension in 5 (27.8%).

Conclusion

Conclusion. CF siblings, despite the same genotype, similar environmental conditions, and high risk of cross-infection, are characterized by wide phenotypic heterogeneity. Aside from the pathogenic CFTR variants, there are other genetic (modifier genes) and epigenetic (microRNA, DNA methylation) factors that could contribute to the clinical features of cystic fibrosis.

Contribution

Contribution.Krasnovidova A.E., Simonova О.I., Chernevich V.P. — research concept and design of the study;Krasnovidova A.E., Pakhomov A.V., Reykh А.P. — сollecting and processing of the material;Krasnovidova A.E. — statistical processing;Krasnovidova A.E. Pushkov А.А. — text writing;Krasnovidova A.E., Pushkov А.А., Simonova О.I. — editing.All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article.

Acknowledgement

Acknowledgement. The study had no sponsorship.

Conflict of interest

Conflict of interest. The authors declare no conflict of interest.

Received

Received: April 18, 2023Accepted: May 16, 2023Published: June 27, 2023

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