Introduction

Severe combined immunodeficiency (SCID) represents a wide class of primary immunodeficiency diseases with various genetic etiologies and some of them have wide variety of clinical characteristics connected with their specific mutations. As a rule, all types of SCID are described by the absence of autologous T-cells, the risk of developing life-threatening infections. After the detection of the gene that encodes the γ-chain (Υc) of the interleukin-2 lymphocyte receptor (IL-R) as the cause of the X-linked SCID that occurred more than two decades ago, more than a dozen other types of SCID were identified by genotype and related immune and clinical characteristics with distinguishing features of pathogenesis with respect to disorders in T, B and NK cells. SCID IL2RG stays the most common X-linked type, as all other methods of transmitting genetic data in SCID are characterized as autosomal recessive. In spite of the development and accessibility of genetic diagnostic and immunological screening and increased public popularization of health for primary immunodeficiency diseases with the recent performing examination for chosen types SCID [1–6].

Strong combined immunodeficiency disorder usually develops in infancy or early childhood and is connected with severe bacterial, viral and/or fungal infections due to mutations in the genes that are responsible for the development of T-cells and B-cells sometimes. However, patients who have hypomorphic mutations in genes, that are classically associated with SCID, may show milder clinical signs, which include T-cell lymphopenia and adult immunodeficiency [7–11].

The first CORO1A gene encoding mutation was identified in a patient with T-B + NK + SCID.

Coronin-1A deficiency is one of the latest forms of SCID that were recently detected [12–16].

Coronin-1A is key actin cytoskeleton biological regulator, counteracting the polymerization of F-actin and the mobilization of calcium ions through signaling processes of calcininurin, especially in T cells. In addition, it has also been reported as a regulator of different signaling ways including TGF-beta/SMAD3, involved into the control of cell growth and development [17–21].

The special immunophysiological role of coronin 1 includes promoting survivance that is specific for mycobacterial organisms in macrophages by attracting and localizing Coronin 1 in phagosomes containing mycobacteria. However, in this case the advantages for the body of the host are unclear. Mice with Coronin-1A deficiency had problems with T-cell activating and calcium control, also the life-staining process of T-cell migration from the thymus. With a deficiency of human coronin-1A, the thymus was described as functioning, despite thymus-related defects with deep T-cell lymphopenia and abnormal naive subpopulations of T-cells. Although the TB + NK + immunophenotype was described both for mice and people with CORO1A deficiency, defective outcomes for discrete subpopulations of lymphocytes have not yet been completely described by the CORO1A mutations clinical phenotypes [22–28].

All human mutations in CORO1A that were described, lead to a complete lack of protein expression, which leads to severe combined T-B + NK + immunodeficiency or combined immunodeficiency, which shows itself in childhood as recurrent viral infections and additional signs that include EBV-associated lymphoproliferative diseases and shortening of telomeres [29–33].

Recently, it was found that CORO1A deficiency, besides being origin of severe combined immunodeficiency, also leads to the development of a non-classical type of epidermodysplasia verruciformis [34–39].

According to S. Huang et al., 2018 verruciform epidermodysplasia (VE) is a rare genodermatosis, connected with the EVER1/TMC6 and EVER2/TMC8. These genes are involved in T-cells mediated immunity against human papillomavirus (HPV). VE is identified by scaling hyper- and hypopigmented spots and papules in early childhood, located on face, neck, arms and trunk. According to S. Huang et al., 2018 heterogenic (more than 20 formations on different body area) generalized verrucosis is diffuse skin lesion, among the causes the most important is HPV. According to S. Huang et al., 2018 generalized verrucosis is common for immunocompromised conditions (condylomas, hypogammaglobulinemia, various infections, myelocatexia syndrome) and verruciform epidermodysplasia. According to S. Huang et al., 2018 VE is associated with specific subtypes HPV (3, 5, 8, 9, 10, 12, 14, 15, 17, 19-25, 28, 29, 36, 46, 47, 49, and 50), which is principal in its diagnostics [40–45].

Material and Methods

We observed a patient, a 13-years old girl, who attended the clinic complaining of rash on the skin of the upper and lower extremities, without subjective feelings.

First, the patient noticed the appearance of rash on the skin of the right foot in May 2016, without any obvious reasons. When the patient contacted a dermatologist at her place of residence, she was diagnosed with Psoriasis. The patient was treated on an ambulatory basis. The treatment passed predominantly with topic glucocorticosteroids without any significant effect. In January of 2017 the patient was consulted at the Institute of Allergology and Clinical Immunology — she was recommended consultation and examination Deep Fungal Diseases department. In September 2017, she was consulted in the outpatient department of «Russian Children’s Clinical Hospital», with a diagnosis «Lymphoma?» Histological examination was recommended. In December 2017, the patient was examined by a TB doctor to exclude specific skin lesions.

Examination revealed that the pathological process on the skin was of widespread, inflammatory and symmetrical character. It was located on the skin of the upper and lower extremities, was represented by dense, smooth, hemispherical and slightly flattened shiny dermal nodules and pinkish nodes. All of the nodes and nodules were located in circle and in groups in the form of a half ring. Ulcer lesions with a tendency to eccentric growth were also detected. The edges of the ulcers were raised in the form of a roller, surrounded by a zone of hyperemia. Hair, nail plates and mucosa are intact (Fig. 1, 2).

Рис. 1. Пациентка А., 13 лет. Клинические проявления гранулематозных поражений кожи нижних (а—г) и верхних конечностей (д), связанных с вирусными бородавками.

Рис. 2. Пациентка А., 13 лет. Патологический процесс представлен плотными, гладкими полусферическими кожными узелками и узлами розового цвета, расположенными по кругу и группами в виде полукольца.

Отмечаются также изъязвленные участки со склонностью к эксцентрическому росту. Края язв приподняты в виде валика, окруженного зоной гиперемии с гнойными выделениями.

During the patient intake, next information about past diseases was: chickenpox, severe course. Acute left-sided polysegmental pneumonia. Herpetic infection: herpes simplex virus type 6. Acute viral-bacterial conjunctivitis. Treatment in the emergency of Tushino children’s city hospital. Bilateral polysegmental pneumonia, severe course. Chronic pansinusitis, during 2016–2017, endoscopic pansinusotomy was performed three times in the conditions of the ENT department of the Morozov Children’s Hospital. Once a month, the patient receives courses of conservative treatment during exacerbation, with the use of antibacterial drugs, both on an outpatient basis and in a daily hospital. Last admission to hospital was in December 2017.

Regarding the underlying disease, the patient repeatedly received therapy with topical corticosteroids (Betamethasonum, Clobetasolum, Naphtaderm), topical antibacterial therapy (Fucidin), with non-significant positive effect.

In January–February 2018 he patient received a course of systemic antimycotic therapy (Itraconazolum 100 mg, 2 times a day, for 14 days), zinc paste, without any effect.

In March 2018, after consulting an infectious disease specialist, she started a course of systemic antibiotic therapy (Biseptol 960 mg 2 times a day, for 14 days), immunomodulators (Immunomax 200 IU No. 6), with a positive effect in the form of a lack of progression of the skin process (according to the patient’s mother).

During an extended examination, the patient was diagnosed changes in blood immunological parameters — significant lymphopenia, a decrease of T-lymphocytes 534 (N: 1000-2200) CD3 +, T-helper cells CD3 +/CD4 + 24 (N: 31-52) T-cytotox.lymph. CD3 +/CD8 + 307 (N: 330-920); Immuno-regulatory index CD3 +/CD8 0.75 (N: 1.1–1.4); screening for type VI virus by EIA IgG 1/2000; by the IIT method — positivel; Screening for Epstein-Barr virus by EIA IgG 1/2600; IIT method — negative; Examination of cytomegalovirus infection by EIA IgG 1/3000; IIT method — negatively.

Pustule culture discharge for conditionally pathogenic microflora and actinomycetes discovered an abundant growth of Staphylococcus aureus and acinetobacter baumanii, sensitivity to doxycycline and ciprofloxacin was discovered.

During a duplex scan of the veins of the lower extremities, signs of chronic lymphadenitis of the upper third of the right thigh, lymphostasis of the lower third of the right lower leg, and patency of the saphenous and deep veins were preserved.

Histological examination of biopsy samples of the affected areas of the skin was carried out multiple times, in which a granulomatous lesion was discovered, including tuberculoid granulomas. Based on clinical and medical history data, an association with primary immunodeficiency was suggested.

Histological examination data from August 2018 showed granulomatous inflammation with the formation of palisade necrobiotic (including perforating) and tuberculoid granulomas. Acid-resistant bacteria and fungal microorganisms were not found when stained with Ziehl-Nielsen and GMS (Fig. 3).

Рис. 3. а — окраска гематоксилином и эозином, ×50. Погружные наросты эпидермиса с образованием свищевого тракта; б — окраска гематоксилином и эозином, ×100. Широкая зона некробиоза, разделенная валом гранулематозного воспаления.

In August 2018, the patient was sent to pass a genetic test (Table), as a result of which a single nucleotide c.19C> T in the homozygous state was detected in the CORO1A gene, leading to the replacement of the amino acid p.Arg7Cys. This option is not found in the databases of human allelic variants and is not described in the literature as pathogenic. Computer programs for predicting pathogenicity characterize this option as probably pathogenic: PolyPhen2_HumDiv — probably damaging (1); PolyPhen2_HVAR — probably damaging (1); SIFT — damaging (0); PROVEAN — deleterious (–7.04); UMD Predictor — pathogenic (96). According to cumulative data, the replacement is classified as an option with unclear clinical significance.

The conclusion regarding the results of high-performance DNA sequencing (Panel «Immunological») is presented in Table.

Результаты высокоэффективного секвенирования ДНК (панель «Иммунологическая»)

Such homozygous and compound heterozygous CORO1A gene mutations are described in the history of patients with type 8 autosomal recessive immunodeficiency (Immunodeficiency 8, OMIM # 615401), which is characterized by T-cell lymphopenia.

It was recommended to provide the biomaterial of both parents for research in order to establish the carriage of the proband variant found in the CORO1A gene from father and mother.

In November 2018, a consultation was held consisting of the chief specialist of a dermatovenerologist and cosmetologist of Moscow Health Department, the director of Moscow scientific and practical center of dermatovenerology and cosmetology, prof., Doctor of medical sciences, N. Potekaev, chief specialist of an allergy-immunology department of Moscow Health Department, chief specialist of allergy department and separate business unit of pediatric research institute of Russian national research medical university named after N. Pirogov, A. Pampura, deputy director of the Institute of Hematology, Immunology and Cell Technologies of National Medical Research Center for Pediatric Hematology, Oncology and Immunology, Doctor of Medical Sciences, prof. A. Shcherbina.

Data of both parents, regarding genetic screening, was performed at the consilium. Her father was revealed a similar replacement of one nucleotide c.19C > T in the homozygous state, leading to the replacement of the amino acid p.Arg7Cys.

Later the patient received immunoglobulin in the Children’s State Clinical Hospital No. 9 named after G.N. Speransky of Moscow Health Department every month with positive dynamics in immunological parameters of blood and skin process (Fig. 4). The patient was prepared for bone-marrow transplantation at the Institute of Hematology, Immunology and Cell Technologies of National Medical Research Center for Pediatric Hematology, Oncology and Immunology.The patient was in the immunology department of National medical investigatory center of children hematology, oncology and immunology named after Dmitry Rogachev of the Ministry of Health of the Russian Federation since 17.05.21 till 16.06.21, where allogenic transplantation by hematopoietic stem cell from of peripheral blood from haploidentical relative donor (mother) with processing of transplantat TCRab/СD19 depletion 23.06.21 was done, the patient was in the day hospital from 03.08.21 till 28.12.21 with clinical diagnosis: Primary immunodeficiency combinatory: deficiency COR01A (mutation in gene COR01A c.19C>T, p.Arg7Cys in homozyhous state).ICD-10 D84.8. The clinical improvement of the lesions was demonstrated (Fig. 5).

Рис. 4. На фоне комплексного лечения иммуноглобулином и топическими кортикостероидами наблюдалась положительная динамика.

Рис. 5. Клинические проявления после лечения.

Conclusion

Presented clinical case is unique, it illustrates the long and difficult period of diagnosis, the complicity of differential diagnosis, severe clinical picture, different methods of diagnostics including DNA sequencing, interdisciplinary approach and successful treatment which resulted in great improvement.

Authors’ contributions:

Conception and design of the study: N.N. Potekaev, O.V. Zhukova, A.N. Pampura, A.Y. Scherbinina, S.B. Zimin, D.N. Serov, E.A. Gauf, O.V. Lupashko, S.I. Bobko, Miakova N.V., Pshonkin A.V., Shpizina I.P.

Collection and statistical analysis: N.N. Potekaev, O.V. Zhukova, A.N. Pampura, A.Y. Scherbinina, S.B. Zimin, D.N. Serov, E.A. Gauf, O.V. Lupashko, S.I. Bobko, Miakova N.V., Pshonkin A.V., Shpizina I.P.

Writing of the text: N.N. Potekaev, O.V. Zhukova, A.N. Pampura, A.Y. Scherbinina, S.B. Zimin, D.N. Serov, E.A. Gauf, O.V. Lupashko, S.I. Bobko, Miakova N.V., Pshonkin A.V., Shpizina I.P.

Editing: N.N. Potekaev, O.V. Zhukova, A.N. Pampura, A.Y. Scherbinina, S.B. Zimin, D.N. Serov, E.A. Gauf, O.V. Lupashko, S.I. Bobko, Miakova N.V., Pshonkin A.V., Shpizina I.P.

Участие авторов:

Концепция и дизайн исследования: Н.Н. Потекаев, О.В. Жукова, А.Н. Пампура, А.Ю. Щербина, С.Б. Зимин, Д.Н. Серов, Е.А. Гауф, О.В. Лупашко, С.И. Бобко, Н.В. Мякова, А.В. Пшонкин, И.П. Шпицина

Сбор и обработка материала: Н.Н. Потекаев, О.В. Жукова, А.Н. Пампура, А.Ю. Щербина, С.Б. Зимин, Д.Н. Серов, Е.А. Гауф, О.В. Лупашко, С.И. Бобко, Н.В. Мякова, А.В. Пшонкин, И.П. Шпицина

Написание текста: Н.Н. Потекаев, О.В. Жукова, А.Н. Пампура, А.Ю. Щербина, С.Б. Зимин, Д.Н. Серов, Е.А. Гауф, О.В. Лупашко, С.И. Бобко, Н.В. Мякова, А.В. Пшонкин, И.П. Шпицина

Редактирование: Н.Н. Потекаев, О.В. Жукова, А.Н. Пампура, А.Ю. Щербина, С.Б. Зимин, Д.Н. Серов, Е.А. Гауф, О.В. Лупашко, С.И. Бобко, Н.В. Мякова, А.В. Пшонкин, И.П. Шпицина

Авторы заявляют об отсутствии конфликта интересов.