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Clinical case
YffK:616-0569.7-002.78-008.9-07-085-037 DOI: 10.26565/2313-6693-2021-41-13
LESCH-NYHAN SYNDROME - LATE DIAGNOSIS OF RARE DISEASE: CLINICAL CASE
Khaniukov O. O., Chornyi V. I., Yevstihnieiev I. V., Hutnik I. O., Smolianova O. V., Romuz N. A., Esterkina K. V., Pervieieva K. I.
Background. Lesch-Nyhan syndrome is inherent X-linked recessive genetic disorder with decreased activity of hypoxanthine-guanine phosphoribosyltransferase (HGPRT). The disease is characterized by presence of the classical triad: hyperuricemia, neurological and behavioral changes. In the article we present a clinical case of Lesch-Nyhan syndrome first diagnosed only at 16 years old despite the fact that the clinical clues were already found at the patient's early age.
Case presentation. An 18-year-old Caucasian man was admitted to the rheumatology department because of gouty arthritis. In neonatal period he was diagnosed with mild intrauterine growth restriction by hypoplastic type. Uric acid crystals were found in our patient's urine at 6-month-old. In the first year of life, delayed motor development was noted together with permanent neurological changes which were referred to rickets. During school years, severe dysgraphia, dyslexia, dysarthria, logoneurosis warranted observation by a speech therapist. At his 12 he had been diagnosed with nephrocalcinosis, at 14 - with chronic kidney disease and symptomatic arterial hypertension. The family history was remarkable for gout in grandmother and great-grandmother, chronic pyelonephritis - in mother, urate nephropathy - in both brothers. In physical examination hyperemia and edema of the left first metatarsophalangeal joint, left ankle defiguration, funnel chest, gynecomastia, tophi on the ears were noted. On examination, some neurological disorders and mild cognitive impairment were found. In investigations hyperuricemia, arthritis of the first metatarsophalangeal joint, diffuse changes in the renal parenchyma with impaired renal excretory function were detected. Despite the clues in patient's anamnesis, objective examination and additional investigation, as well as the presence of a family anamnesis suggesting the hereditary nature of hyperuricemia, the diagnosis of HGPRT deficiency was not made until the age of 16 years.
Conclusion. The presence of Lesch-Nyhan syndrome can be assumed with the progression of muscle tone impairment and movement disorders in a child after the first six months of life in combination with high plasma uric acid concentration and its increased urinary excretion. Difficulties in the syndrome diagnosis are associated not only with a rare occurrence, but with a slight or moderate degree of central nervous system impairment that is often related by doctors to rickets or delivery trauma, as well as low accessibility of molecular genetic testing.
KEY WORDS: Lesch-Nyhan syndrome, hyperuricemia, primary gout, clinical case INFORMATION ABOUT AUTHORS
Khaniukov Oleksii, MD, PhD, Professor, Head of the Department of Internal Medicine 3, State Institution «Dnipropetrovsk Medical Academy of the Ministry of Health of Ukraine», 9, Vernadsky str., Dnipro, Ukraine, 49044, email: [email protected], ORCID ID: https://orcid.org/0000-0003-4146-0110
Chornyi Valerii, General Director of Communal Non-profit Enterprise «City Clinical Hospital № 11» Dnipro City Council», 1, Hanny Barvinok str., Dnipro, Ukraine, 49000
Yevstihnieiev Ihor, PhD, Assistant of the Department of Internal Medicine 3, State Institution «Dnipropetrovsk Medical Academy of the Ministry of Health of Ukraine», 9, Vernadsky str., Dnipro, Ukraine, 49044, email: [email protected], ORCID ID: https://orcid.org/0000-0001-5383-2562
Hutnik Ihor, PhD, internal medicine doctor, Communal Non-profit Enterprise «City Clinical Hospital № 2» Dnipro City Council», 53, Sergei Nigoyan av., Dnipro, Ukraine, 49000, email: [email protected], ORCID ID: https://orcid.org/0000-0001-8512-6013
Smolianova Oleksandra, Assistant of the Department of Internal Medicine 3, State Institution «Dnipropetrovsk Medical Academy of the Ministry of Health of Ukraine», 9, Vernadsky str., Dnipro, Ukraine, 49044, email: [email protected], ORCID ID: https://orcid.org/0000-0002-8654-381X
Romuz Nataliia, Assistant of the Department of Internal Medicine, V. N. Karazin Kharkiv National University, 6, Svobody sq., Kharkov, Ukraine, 61022, email: [email protected], ORCID ID: https://orcid.org/0000-0001-6524-889X
Esterkina Kateryna, rheumatologist, Communal Non-profit Enterprise «City Clinical Hospital № 11» Dnipro City Council», Dnipro, Hanny Barvinok str., 1, 49000
© Khaniukov O. O., Chornyi V. I., Yevstihnieiev I. V., Hutnik I. O., Smolianova O. V., Romuz N. A., 115
Esterkina K. V., Pervieieva K. I., 2021
Pervieieva Kateryna, intern, State Institution «Dnipropetrovsk Medical Academy of the Ministry of Health of Ukraine», 9, Vernadsky str., Dnipro, Ukraine, 49044
BACKGROUND
The incidence of gout is rare in childhood, and most children with hyperuricemia have an underlying disease, such as metabolic or genetic disease, acute conditions, malignant disorders, as well as drug side effects and predisposing dietary habits [1, 2]. Thus, the detection of hyperuricemia in child should alert the practitioner and force him to the search for possible cause in a particular patient. In the context of modern preventive medicine, special attention should be drawn to the timely detection of primary gout, in particular, its earliest manifestation - hyperuricemia [1, 2]. In around 80 % of cases gout can be characterized as a primary disease associated with genetic defects in the enzymes regulating purine metabolism, and first signs of the disturbance could be seen in early childhood [2].
Lesch-Nyhan syndrome is inherent X-linked recessive genetic disorder, which main pathogenetic link is the expression disturbance of hypoxanthine-guanine phosphori-bosyltransferase (HGPRT) - specific enzyme involved in purine recycling [3-8]. The disease is characterized by presence of the classical triad: hyperuricemia, neurological and behavioral changes [2-6, 8, 9].
In case of HGPRT deficiency, the process of free guanine and hypoxanthine reuse in the synthesis of guanosine monophosphate and inosine monophosphate is broken, resulting in more rapid conversion of guanine and hypoxanthine into uric acid. This, consequently, leads to hyperuricemia and gout development. Neurological disorders in Lesch-Nyhan syndrome are thought to be caused by a disturbance of neurotransmitters synthesis in the brain dopaminergic systems, which explains the behavioral and motor disorders in such patients [3-6, 8-10]. Kidneys affection is characterized by a similar to gouty nephropathy clinical picture and includes urate crystalluria, recurrent pyelonephritis on the urolithiasis background and, if left untreated, it leads to the development of chronic kidney failure [5, 8].
In the article we present a clinical case of Lesch-Nyhan syndrome first diagnosed only at 16 years old despite the fact that the classical clinical clues were already found at the patient's first year.
CASE PRESENTATION
An 18-year-old Caucasian man was admitted to the rheumatology department with complaints of pain, swelling, hyperemia of the left first metatarsophalangeal joint and the left ankle swelling accompanied by limitation of active and passive movements in both joints.
According to the anamnesis, the child was born from the first pregnancy threatened by miscarriage in the first trimester, polyhydramnios; delivery on time. Birth weight - 2600 g, height - 48 cm, head circumference 32 cm, chest circumference 31 cm. Neonatologist conclusion: mild intrauterine growth restriction by hypoplastic type.
At the age of 6 months, during inpatient treatment for bilateral otitis media patient first was diagnosed with metabolic nephropathy (uric acid crystals were found in the urine analysis). During the hospitalization he was consulted by a neurologist who confirmed hyperexcitability syndrome, initial manifestations of rickets.
In the first year of life, delayed motor development was noted (began to crawl at 11 months, walk at 18 months) together with permanent neurological changes in the form of pronounced hypotonia of the upper and lower extremities. During school years, he was observed by a speech therapist due to severe dysgraphia, dyslexia, dysarthria, logoneurosis. He was diagnosed with nephrocalcinosis at 12 years. At 14 years the I stage of chronic kidney disease and symptomatic arterial hypertension were first established. Since then he has been constantly taking enalapril 5 mg per day. At his 16 hyperparathyroidism was revealed. Same year, 2017, he was examined in the clinic «Ohmatdyt» in Kiev, where a genetic testing was carried out and Lesch-Nyhan syndrome was diagnosed without description of the mutation nature. The treatment with febuxostat 120 mg daily and enalapril 5 mg daily were prescribed. The level of uric acid from 2017 to 2019 years has varied from 400 to 700 ^mol/L, creatinine - from 90 to 135 ^mol/L.
The family history was remarkable for gout in grandmother and great-grandmother, chronic pyelonephritis - in mother, urate nephropathy -in both brothers.
On examination, the general condition was edema of the left first metatarsophalangeal
satisfactory. Body weight - 60 kg, height - 175 joint, left ankle defiguration. Subcutaneous
cm. Body mass index was 19.59 kg/m2. He tophi on the ear (Picture 1). Gynecomastia
limped when walking because of pain in the (Picture 2). Funnel chest (Picture 3). small joints of the left foot. Hyperemia and
\ \
v \
Picture 1. Subcutaneous tophi on the ear
Picture 2. Gynecomastia
Psycho-neurological status. The patient was oriented in time, place and person. His mood appeared labile. There was no evidence of speech disorders. Cranial nerves examination was unremarkable. Upper and lower limbs muscle strength was 5 from 5 grades. The deep tendon and periosteal reflexes of the upper and lower limbs were normal. Pathologic reflexes (Babinsky, Oppenheim, Schaefer, Chaddock) were negative bilaterally. Plastic (extrapyramidal) symmetrical muscular hypertonicity in the upper extremities with resting tremor of their distal part was found together with positive Negro's phenomenon, Noik-Ganev's phenomenon and Formann's symptom. In the lower extremities -symmetrical normotonus. Coordination: finger-to-nose and heel-to-knee tests were performed confidently on both sides; the Romberg test was negative. When walking, there was a slight brady- and oligokinesia without postural instability. Sensation disorders were not found. The patient also had moderate cognitive impairments: the nominative function of speech was impaired, there was a working memory deficit due to coding disturbances especially in the tasks involving several functions simultaneously; mild constructive, verbal and executive dysfunctions. Visual-spatial praxis
and «frontal» functions were normal. Neuropsychological testing with the Montreal Cognitive Assessment scale 18 points; Eysenck's test result was 71 points; according to the depressive states scale by V. Zung (adaptation of T. I. Balashova), the patient had a «state without depression» (40 points), the neurotization level according to L. I. Wasserman was 35 %.
Additional investigations. Laboratory data: uric acid level - 550 ^mol/L, creatinine 86 ^mol/L, glomerular filtration rate -104 ml/min/1,73m2. Radiography of the left foot: marginal growths of the first nail phalanx base, narrowing of the first toe interphalangeal joint, the restructuring of the bone of the first toe main phalanx base (compatible with arthritis of the 2nd degree). Ultrasound of the urinary tract and prostate: prominent diffuse changes in the renal parenchyma, right-sided nephroptosis; bladder and prostate were unremarkable. Excretory urography: indirect signs of inflammatory kidney disease with impaired renal excretory function.
Clinical diagnosis: Lesch-Nyhan syndrome: chronic gouty arthritis, recurrent course, exacerbation stage, activity II, with a predominant affection of the small joints of the left foot, left ankle joint, with the peripheral
tophi, X-ray stage II, functional impairment of joints I degree. Chronic kidney disease I stage: gouty nephropathy, nephrocalcinosis, urinary syndrome, symptomatic arterial hypertension. Chronic renal failure with impaired excretory function of the kidneys. Encephalopathy with moderate cognitive dysfunction, dysarthria.
DISCUSSION
In the «classic» variant of Lesch-Nyhan syndrome (residual activity HGPRT ~ 1.5 %) patients' mean duration of life is about 20-30 years. With moderate extrapyramidal insufficiency (residual activity HGPRT ~ 8 %) life expectancy is much longer, patients are teachable and can acquire some specialties [3, 5, 7-9]. However, in case of late diagnosis, neurological symptoms, nephrolithiasis, chronic renal failure progress resulting in patient's disability [11]. Neurological symptoms can manifest by varying degree of severity of extrapyramidal and pyramidal motor dysfunction [5, 10]. Our patient's neurological manifestations correspond to a moderate degree of extrapyramidal insufficiency and motor dysfunction, that should be characterized as a manifestation of basal ganglia lesions [10]. Hyperuricemia in his case is accompanied by clinical manifestations of gout. According to literature, the above symptomatology corresponds to the residual activity of HGPRT « 8 % [3, 5].
It is important for a pediatric neurologist to know that Lesch-Nyhan syndrome is often hidden under the guise of cerebral palsy clinical manifestations [3, 5, 8]. However, unexplained persistent hyperuricemia and progressive urate nephropathy require explanation, and could help in early diagnosis of the syndrome [11]. Uric acid crystals were primary found in our patient's urine at 6-month-old. At his 12 he had been diagnosed with nephrocalcinosis, at 14 -
with chronic kidney disease and symptomatic arterial hypertension. Despite these clues together with presence of family anamnesis suggesting hereditary character of hyperuricemia, the diagnosis of HPRT deficiency was not made until the age of 16 years. The interaction of a family doctor, pediatric neurologist, rheumatologist, genetics is extremely important and necessary for the earliest possible diagnosis [4]. Difficulties in the syndrome diagnosis are associated not only with a rare occurrence, but frequently with a slight or moderate degree of central nervous system impairment that is often related by doctors to rickets or delivery trauma, as well as low accessibility of molecular genetic studies [4, 5].
The diagnosis can be confirmed by detecting a mutation in the HGPRT1 gene using direct automatic sequencing of the gene coding region. An alternative method of the diagnosis confirmation is the study of the HGPRT enzyme activity in erythrocytes, fibroblast or lymphoblast cultures [4]. In the presented case, the diagnosis was confirmed by a genetic method.
CONCLUSION
The presence of Lesch-Nyhan syndrome can be assumed with the manifestation and progression of muscle tone impairment and movement disorders in a child after the first six months of life in combination with high plasma uric acid concentration and its increased urinary excretion. In order to monitor the effectiveness of hyperuricemia correction and prevention of possible complications, patients with Lesch-Nyhan syndrome need constant supervision from a family doctor with periodic consultation with a nephrologist, a neurologist and a rheumatologist.
REFERENCES
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2. Kubota M. Hyperuricemia in Children and Adolescents: Present Knowledge and Future Directions. J Nutr Metab. 2019; 2019: 3480718. https://doi.org/10.1155/2019/3480718
3. Tewari N, Mathur V, Sardana D, Bansal K. Lesch-Nyhan syndrome: The saga of metabolic abnormalities and self-injurious behavior. Intractable Rare Dis Res. 2017 Feb; 6 (1): 65-8. https://doi. org/10.5582/irdr. 2016.01076
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8. Eliseev MS, Barskova VG. Bolezn' Lesha-Nikhena: klinicheskie proyavleniya i varianty techeniya, analiz sobstvennogo opyta. Modern Rheumatology Journal. 2010; (4): 47-52. https://doi.org/10.14412/1996-7012-2010-620 [in Russian]
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11. Doucet BP, Jegatheesan D, Burke J. Late diagnosis of Lesch-Nyhan disease variant. BMJ Case Rep. 2013 Dec 10;2013:bcr2013201997. https://doi.org/10.1136/bcr-2013-201997
СИНДРОМ ЛЕША-Н1ХАНА - П1ЗНЯ ДИАГНОСТИКА Р1ДК1СНОГО ЗАХВОРЮВАННЯ:
КЛШ1ЧНИЙ ВИПАДОК
Ханюков О. О., Чорний В. I., Свстинеев I. В., Гутшк I. О., Смольянова О. В., Ромуз Н. А., Естеркта К. В., Первеева К.
Вступ. Синдром Леша-Шхана е вродженим Х-зчепленим рецесивним генетичним розладом 3i зниженою актившстю гшоксантин-гуашнфосфорибозилтрансферази. Хвороба характеризуеться наявшстю класично! трiади: гiперурикемiя, неврологiчнi та поведiнковi розлади. У статтi ми представляемо клшчний випадок синдрому Леша-Нiхана, вперше дiагностований у пацiента лише у 16 рокв, незважаючи на те, що «клшчш тдказки» вже були виявлеш в ранньому вiцi.
Клiнiчний випадок. 18^чний чоловiк звернувся до ревматолопчного вiддiлення через подагричний артрит. У неонатальному перiодi у нього дiагностували затримку внутрiшньоутробного розвитку по гшопластичному типу. У 6-мiсячному вiцi в сечi були виявленi кристали сечово! кислоти. У перший рiк життя вiдзначалася затримка моторного розвитку разом iз постiйними неврологiчними змiнами, як були розцiненi як прояви рахиу. У шкiльнi роки важка дисграфiя, дислексiя, дизартрiя, логоневроз вимагали спостереження з боку логопеда. У 12 роив йому був дiагностований нефрокальциноз, у 14 - хрошчне захворювання нирок та симптоматична артерiальна гiпертензiя. У сiмейному анамнезi: подагра у бабус та прабабусi, хронiчний телонефрит - у матерi, уратна нефропатая - у обох братiв. При фiзикальному обстеженнi вiдзначалися гiперемiя та набряк лiвого першого плюснефалангового суглоба, деформащя лiвоi щиколотки, воронкоподiбна грудна клiтина, гiнекомастiя, тофуси на вухах. Шд час огляду було виявлено низку неврологiчних порушень та ж^рний когнiтивний розлад. У додаткових дослщженнях - гiперурикемiя, артрит першого плюснефалангового суглоба, дифузш змiни нирково! паренхши з порушенням видiльноi функцii нирок. Попри тдказки в анамнезi пащента, об'ективному та додатковому обстеженнях, а також наявшсть сiмейного анамнезу, що сввдчить про спадковий характер гшерурикемп, дiагноз дефiциту ГФРТ був поставлений лише у вiцi 16 роюв.
Висновок. Наявнiсть синдрому Леша-Нiхана можна припустити при прогресуваннi порушення м'язового тонусу та рухових розладiв у дитини пiсля перших шести мкящв життя у поеднаннi з високою концентрацiею сечово! кислоти в плазмi та ii пiдвищеною екскрецiею з сечею. Труднощi в дiагностицi синдрому пов'язат не тiльки з рвдюсними характером захворювання, але й з незначним або помiрним порушенням функци центральноi нервовоi системи, яке лiкарi часто пов'язують з рахiтом або пологовою травмою, а також низькою доступнiстю молекулярно-генетичного тестування.
КЛЮЧОВ1 СЛОВА: Синдром Леша-Шхана, гiперурикемiя, первинна подагра, клшчний випадок ИНФОРМАЦ1Я ПРО АВТОР1В
Ханюков Олекс1й Олександрович, д.мед.н., професор, зав^вач кафедри внутршньо1 медицини 3, Державний заклад «Дншропетровська медична академшя Мiнiстерства охорони здоров'я Украши», вул. Вернадського, 9, Дншро, Укра1на, 49044, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0003-4146-0110 Чорний Валерш 1ванович, генеральний директор, Комунальне некомерцiйне пiдприемство ««Мiська кшшчна лiкарня № 11» Днiпровськоi мюько1 ради», вул. Ганни Барвiнок, 1, Дншро, Украша, 49044
Евспгнеев 1гор Володимирович, к.мед.н., асистент кафедри внутршньо'1 медицини 3, Державний заклад «Дшпропетровська медична академiя Мiнiстерства охорони здоров'я Украши», вул. Вернадського, 9, Дншро, Украша, 49044, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0001-5383-2562 Гутшк 1гор Олександрович, к.мед.н., лiкар-терапевт, Комунальне некомерцiйне шдприемство ««Мiська клiнiчна лiкарня № 2» Дншровсько1 мюько'1 ради», пр. Серия Кгояна, 53, Днiпро, Украша, 49000, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0001-8512-6013
Смольянова Олександра Вiкторiвна, асистент кафедри внутршньо'1 медицини 3, Державний заклад «Дшпропетровська медична академiя Мшютерства охорони здоров'я Украiни», вул. Вернадського, 9, Дншро, Украiна, 49044, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0002-8654-381X Ромуз Натажя Андривна, асистент кафедри внутршньо'1 медицини, Харювський нацiональний унiверситет iменi В. Н. Каразiна, пл. Свободи, 6, Харюв, Украша, 61022, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0001-6524-889X
Естеркша Катерина Вадишвна, лiкар-ревматолог, Комунальне некомерцшне пiдприeмство «Мiська клiнiчна лiкарня № 11» Дншровсько'1 мюько'1 ради», вул. Ганни Барвшок, 1, Днiпро, Украша, 49044
Первеева Катерина, лiкар-iнтерн, Державний заклад «Дшпропетровська медична академiя Мшютерства охорони здоров'я Украши», вул. Вернадського, 9, Дншро, Украша, 49044
СИНДРОМ ЛЕША-НИХАНА - ПОЗДНЯЯ ДИАГНОСТИКА РЕДКОГО ЗАБОЛЕВАНИЯ:
КЛИНИЧЕСКИЙ СЛУЧАЙ
Ханюков А. А., Чорный В. И., Евстигнеев И. В., Гутник И. А., Смольянова А. В., Ромуз Н. А., Эстеркина Е. В., Первеева Е.
Вступление. Синдром Леша-Нихана это врожденное Х-сцепленное рецессивное генетическое заболевание со сниженной активностью гипоксантин-гуанинфосфорибозилтрансферазы. Болезнь характеризуется наличием классической триады: гиперурикемия, неврологические и поведенческие расстройства. В статье мы представляем клинический случай синдрома Леша-Нихана, впервые диагностированного у пациента в 16 лет, несмотря на наличие "клинических подсказок" начиная с раннего возраста.
Клинический случай. 18-летний мужчина обратился в ревматологическое отделение в связи с подагрическим артритом. В неонатальном периоде у него диагностировали задержку внутриутробного развития по гипопластическому типу. В 6 месяцев в моче были обнаружены кристаллы мочевой кислоты. В первый год жизни отмечалась задержка моторного развития вместе со стойкими неврологическими изменениями, которые были расценены как проявления рахита. В школьные годы тяжелая дисграфия, дислексия, дизартрия, логоневроз потребовали наблюдения со стороны логопеда. В 12 лет был диагностирован нефрокальциноз, в 14 - хроническое заболевание почек и симптоматическая артериальная гипертензия. В семейном анамнезе: подагра у бабушки и прабабушки, хронический пиелонефрит - у матери, уратная нефропатия - у обоих братьев. При физикальном осмотре отмечались гиперемия и отек левого первого плюснефалангового сустава, деформация левой лодыжки, воронкообразная грудная клетка, гинекомастия, тофусы на ушах. При осмотре были обнаружены ряд неврологических нарушений и умеренное когнитивное расстройство. С помощью дополнительных исследований обнаружены: гиперурикемия, артрит первого плюснефалангового сустава, диффузные изменения почечной паренхимы с нарушением выделительной функции почек. Несмотря на подсказки в анамнезе пациента, объективном и дополнительных обследованиях, а также наличие семейного анамнеза, свидетельствующего о наследственном характере гиперурикемии, диагноз дефицита ГГФТ был поставлен лишь в возрасте 16 лет.
Выводы. Наличие синдрома Леша-Нихана можно предположить при прогрессировании нарушения мышечного тонуса и двигательных расстройств у ребенка после первых шести месяцев жизни в сочетании с высокой концентрацией мочевой кислоты в плазме и ее повышенной экскрецией с мочой. Трудности в диагностике синдрома связаны не только с редким характером заболевания, но и с незначительным или умеренным нарушением функции центральной нервной системы, которое врачи часто связывают с рахитом или родовой травмой, а также низкой доступностью молекулярно-генетического тестирования.
КЛЮЧЕВЫЕ СЛОВА: Синдром Леша-Нихана, гиперурикемия, первичная подагра, клинический случай
ИНФОРМАЦИЯ ОБ АВТОРАХ
Ханюков Алексей Александрович, д.мед.н., профессор, заведующий кафедрой внутренней медицины 3, Государственное учреждение «Днепропетровская медицинская академия Министерства здравоохранения Украины», ул. Вернадского, 9, Днипро, Украина, 49044, email: [email protected], ORCID ID: https://orcid.org/0000-0003-4146-0110
Чорный Валерий Иванович, генеральный директор, Коммунальное некоммерческое предприятие ««Городская клиническая больница № 11» Днипровского городского совета», ул. Ганны Барвинок, 1, Днипро, Украина Евстигнеев Игорь Владимирович, к.мед.н., ассистент кафедры внутренней медицины 3, Государственное учреждение «Днепропетровская медицинская академия Министерства здравоохранения Украины», ул. Вернадского, 9, Днипро, Украина, 49044, e-mail: [email protected], ORCID ID: https://orcid.org/0000-
0001-5383-2562
Гутник Игорь Александрович, к.мед.н., врач-терапевт, Коммунальное некоммерческое предприятие «Городская клиническая больница № 2» Днипровского городского совета», пр. Сергея Нигояна, 53, Днипро, Украина, 49000, email: [email protected], ORCID ID: https://orcid.org/0000-0001-8512-6013
Смольянова Александра Викторовна, ассистент кафедры внутренней медицины 3, Государственное учреждение «Днепропетровская медицинская академия Министерства здравоохранения Украины», ул. Вернадского, 9, Днипро, Украина, 49044, email: [email protected], ORCID ID: https://orcid.org/0000-
0002-8654-381X
Ромуз Наталия Андреевна, ассистент кафедры внутренней медицины, Харьковского национального университета им. В. Н. Каразина, пл. Свободы, 6, Харьков, Украина, 61022, email: [email protected], ORCID ID: https://orcid.org/0000-0001-6524-889X
Эстеркина Екатерина Вадимовна, врач-ревматолог, Коммунальное некоммерческое предприятие «Городская клиническая больница № 11» Днипровского городского совета», ул. Ганны Барвинок, 1, Днипро, Украина. Первеева Екатерина, врач-интерн, Государственное учреждение «Днепропетровская медицинская академия Министерства здравоохранения Украины», ул. Вернадского, 9, Днипро, Украина 49044
Отримано: 15.12.2020 р. Прийнято до друку: 16.01.2021 р.
