home Drugs Severe combined immunodeficiency in children: possible causes, symptoms and treatments

Severe combined immunodeficiency in children: possible causes, symptoms and treatments

They are characterized by impaired differentiation of stem cells, a block in the maturation of T- and B-lymphocytes and their deficiency. Combined forms of immunodeficiency are more common than selective ones. In combined IDS, the leading role belongs to the defect of T-lymphocytes.

Reticular dysgenesis syndrome characterized by a decrease in the number of stem cells in the bone marrow. Intrauterine fetal death is typical, or children die soon after birth.

"Swiss" type of immunodeficiency characterized by damage to the T- and B-systems and, consequently, a violation of cellular and humoral reactions of immunological defense. The content of B-lymphocytes may meet or exceed the norm, but these cells are not able to secrete immunoglobulins in sufficient quantities.

The disease manifests itself in the first months of life and is often characterized by a malignant course. There is a delay in body weight gain; already in the first days of life, some children develop measles-like rashes on the skin, which may be due to incompatibility reactions with maternal lymphocytes entering the child’s bloodstream through the placenta. Signs of cutaneous candidiasis, diarrhea, and acute interstitial pneumonia develop, becoming protracted and recurrent. Children are very susceptible to viral infections. Significant lymphopenia is detected in the blood, the content of T-lymphocytes is especially low. The content of immunoglobulins of all classes is reduced. The exception is infants with IgG obtained from the mother. Pathognomonic changes in the thymus gland, hypoplasia of the tonsils and lymph nodes. There is an inability to exhibit delayed-type hypersensitivity reactions. Children rarely live past 2 years of age.

Ataxia-telangiectasia syndrome (Louis-Bar syndrome) caused by a maturation defect, decreased function of T-lymphocytes, a decrease in their number in the blood (especially T-helper cells), and deficiency of immunoglobulins (especially IgA, IgE, less often IgG). The syndrome is characterized by a combination of ataxia and other neurological abnormalities with telangiectatic changes in the vessels of the sclera and face. Defeat nervous system manifested by symptoms of loss of functions of the cerebellum, subcortical ganglia, diencephalic region, and pyramidal system. As a result of their lesions, gait disturbances, slowness of voluntary movements, hyperkinesis, vegetative-vascular dystonia. Many suffer from sluggish pneumonia and develop atelectasis, pneumosclerosis and bronchiectasis. Hypoplasia of the thymus gland, lymph nodes, spleen, lymphopenia is detected, IgA is not detected.

The disease is characterized by an autosomal recessive mode of inheritance. The prognosis of the syndrome is unfavorable. About 50% of deaths are caused by chronic damage to the bronchopulmonary system, about 20% by the development malignant processes, which are associated with the loss of functional activity of thymus-dependent lymphocytes and immunological surveillance functions. Some patients live to be 40–50 years old.

Wiskott-Aldrich syndrome is an X-linked disease characterized by combined immunodeficiency in combination with thrombocytopenia and eczema. The disease is the result of a mutation in the gene encoding a protein that is involved in actin polymerization and cytoskeleton formation. The absence of this protein in lymphocytes and platelets of patients leads to the development of thrombocytopenia, dysfunction of T-lymphocytes and regulation of antibody synthesis. The diagnosis of typical forms of Wiskott-Aldrich syndrome can be assumed in male patients in the presence of thrombocytopenia with a decrease in platelet size in combination with eczema and frequent infectious diseases of bacterial, less often viral and fungal etiology. However, mild forms of the disease are often encountered, occurring with thrombocytopenia and hemorrhagic syndrome. varying degrees severity, but without a pronounced infectious syndrome and/or allergic history. There is lymphopenia, mainly due to T-lymphocytes, a decrease in the functional activity of T-lymphocytes, normal or reduced levels of IgG, increased level IgA and IgE. Clinical manifestations of the disease usually debut in the first year of life. Hemorrhagic syndrome in the form of melena, nosebleeds, and hemorrhagic skin rashes are most often present in all patients at the time of diagnosis. Autoimmune anemia, glomerulonephritis, colitis, and immune neutropenia are common. Forecast severe forms unfavorable, children die before the age of 10 years. Infections, hemorrhages or malignant neoplasms of the lymphoreticular system lead to death.

Immunodeficiencies associated with insufficiency

Complement systems

The complement system is represented by proteolytic enzymes and regulatory proteins. There are 20 complementary factors in the blood, the activation of which can be carried out in the classical or alternative way.

With congenital C1 deficiency, activation of the complement system through the classical pathway is impossible. With congenital deficiency of C3b and C5, the processes of phagocytosis and lysis of bacteria are disrupted, which is manifested by repeated purulent infections.

Secondary immunodeficiency- Acquired immunodeficiency syndrome–AIDS– this is an infectious disease from the group of slow infections, caused by the human immunodeficiency virus (HIV), transmitted predominantly sexually, as well as parenterally; is characterized by a profound violation of cellular immunity, resulting in the addition of various secondary infections (including those caused by opportunistic flora) and malignant neoplasms. The causative agent is the T-lymphocyte (lymphotropic) human immunodeficiency virus - HIV. The nucleoid contains two RNA molecules (the viral genome) and reverse transcriptase.

HIV is unstable in external environment and dies at a temperature of 56°C for 30 minutes. Resistant to ionizing radiation and ultraviolet irradiation.

The source of infection is a sick person and a virus carrier. The highest concentration of the virus is found in the blood, semen, and cerebrospinal fluid; in smaller quantities, the virus is detected in the tears, saliva, cervical and vaginal secretions of patients. Currently, 3 routes of infection have been proven: sexual (through homosexual and heterosexual contacts); through parenteral injection of the virus with blood products or using contaminated instruments; from mother to child - transplacental or with milk.

Possessing tropism for CD4 + receptors, the virus attaches to epitopes of the cell membrane, most often T-helper lymphocytes. Then it penetrates inside, where it is integrated into the genetic apparatus of the cell. Using reverse transcriptase, using the chromosomal DNA of the target cell, the virus encodes the production of similar particles until the cell dies. After cell death, the virus colonizes new cells that have CD4 + receptors. In CD4+ helper lymphocytes, HIV can remain latent indefinitely.

The mechanism of death of helper T lymphocytes is the cytopathic effect of the virus, the formation of anti-HIV antibodies and cytotoxic lymphocytes, which cause cytolysis of both damaged and undamaged helper T lymphocytes.

In addition, CD4 + lymphocytes lose the ability to recognize antigen. One of the important clinical signs of the disease is the development of progressive lymphopenia, mainly due to T-helper cells. Quantitative and qualitative changes in T-lymphocytes, as well as damage to macrophages, are accompanied in the initial stage of the disease by primary damage to cellular and, to a lesser extent, humoral immunity.

The disease develops during HIV infection long time. Among the periods of AIDS (HIV +) there are: incubation (asymptomatic carriage); lymphadenopathy syndrome (LAS) or persistent generalized lymphadenopathy; AIDS-associated syndrome (pre-AIDS), or AIDS-associated complex (ASC); acquired immunodeficiency syndrome (AIDS).

The incubation period can last from 6 weeks to 12 years or more. In most cases in incubation period no symptoms of the disease are detected. During this period, the fact of infection can be established by detecting antigen or anti-HIV antibodies in the blood. Many factors can trigger pronounced HIV replication, which leads to massive cell death and the appearance of clinical symptoms. In approximately 20% of cases, acute manifestations of primary HIV infection are observed, developing 3–6 weeks after infection. Its clinical and morphological signs are high and prolonged fever (38–39°C) with damage to the lymph nodes or prominent cervical lymphadenopathy, accompanied by skin rash and more or less pronounced mononucleosis syndrome, which is a common manifestation of acute viral infection.

The period of persistent generalized lymphadenopathy is characterized by persistent, over several months, enlargement of various groups of lymph nodes. Lymphadenopathy is based on nonspecific hyperreactivity of B cells, manifested by follicular hyperplasia of the lymph nodes (enlargement of lymphoid follicles and their light centers). The duration of the stage is 3–5 years.

The AIDS-associated complex, or pre-AIDS, develops against a background of moderate immunodeficiency and is characterized by a decrease in body weight up to 20%, the development of fever, diarrhea, progressive polylymphadenopathy, and repeated acute viral respiratory infections, for example, herpes zoster. This period lasts several years.

The period of acquired immunodeficiency syndrome is accompanied by a sharp loss of body weight, up to cachexia, and the development of dementia. In the end, a sharp depression of the cellular and humoral immunity develops, which is manifested in the clinic by the development of opportunistic infections (viral, bacterial, fungi) and malignant tumors (malignant B-cell lymphomas and Kaposi's sarcoma).

Combined immunodeficiencies include a group of diseases characterized clinically and immunologically by defects in both T and B lymphocytes. Diagnostic criteria usually include onset of the disease in early age in the form of severe, potentially fatal infections, profound impairment of cellular immunity, antibody deficiency and lymphopenia.

Clinically detected: growth retardation and motor development, persistent, sluggish, persistent infections caused by low-virulent microorganisms (for example, Candida, Pneumocystis carinii, Cytomegalovirus), which requires differential diagnosis with HIV infection in infants.

In table 283 presents the main variants of SCID.

Usually, in the first three months of life, the growth and development of children is more or less normal, especially if the BCG vaccination is not given, but then the increase in body weight and length slows down, malnutrition, persistent thrush and trophic disorders of the skin, and diarrhea develop. Characteristic: lymphocytopenia, interstitial pneumonia caused by Pneumocystis carinii, severe infectious processes caused by cytomegalovirus and other herpetic viruses, adenovirus, fungi. Transplacental transfer of maternal lymphocytes can cause graft-versus-host disease in the form of an erythematous or papular skin rash and liver damage.

At laboratory research hypogammaglobulinemia and a decrease in the proliferative activity of lymphocytes are detected. A close to normal number of lymphocytes may be the result of transplacental transfer of lymphocytes from the mother.

Table 283

Severe combined immune deficiency (SCID), type of inheritance and immunological disorders (Kondratenko I.V., 2004)

Immunodeficiency	Type inheritance	Serum immunoglobulins	Circulating lymphocytes
Immunodeficiency	Type inheritance	Serum immunoglobulins	T	IN	N.K.
Reticular dysgenesis	AR	A	And	44	44
RAG1/RAG2 SCIN	AR	And	A	44	N
Omenn syndrome	AR	And	v/ N	44	N/T
Radiosensitive	AR	And	44	44	N
X-linked SCIN	X-clutch	And	44	N/f	44
JAK3 deficiency	AR	And	44	N/T	44
IL-7R deficiency	AR	And	44	N/T	N
CD45 deficiency	AR	4	44	N/T	4
Adenosine deaminase deficiency	AR	And	44	4	4
Purine nucleoside phosphorylase deficiency	AR	4/N	44	4/N	4/n
ZAP70 deficiency	AR	4/N	v(wCD8)	N	N
CD25 deficiency	AR		4	N	N
CD3r deficiency	AR	N	N(vCD3)	N	N
^CD3e deficiency	AR	N	N(4CD3)	N	N
TAP deficiency	AR	N	4(44CD8)	N	N
MHC II deficiency	AR	N	4(44CD4)	N	N

Notes: N - norm; i - decrease; 4th - sharp decline.

RAG1/RAG2 SCID is caused by a mutation of recombination activating genes (RAG1 and RAG2), which initiate the formation of immunoglobulins and T-cell receptors.

CD45 deficiency is characterized by the absence of transmembrane protein kinase.

IL-7R deficiency.

Expression of the receptor for IL-7 is critical for the development of T lymphocytes, but not B lymphocytes.

TAP (Transporter for Antigen Presentation) deficiency is characterized by low expression of HLA class I molecules on the cell surface, selective deficiency IgG2, lack of antibody response to polysaccharide antigens, severe respiratory bacterial infections, granulomatous skin lesions. Late clinical manifestation of immunodeficiency is possible.

CD25 deficiency is caused by a mutation in the IL-2 a-chain gene and leads to impaired T-cell proliferation, apoptosis in the thymus, expansion of autoreactive clones, and lymphoid infiltration of tissues.

Omenn syndrome is a variant of SCID, characterized by the development shortly after birth of generalized erythroderma, alopecia, desquamation of the epithelium, diarrhea, malnutrition, hepatosplenomegaly, hypereosinophilia and a pronounced increase in the concentration of IgE in the blood. The number of Th2 cells is increased in the blood and tissues. The levels of B-lymphocytes, immunoglobulins A, M, G, production of IL-2, INFy are sharply reduced.

Nezelof syndrome is a variant of SCID with normal levels of immunoglobulins and preserved lymphoid tissue, but sharply reduced levels of CD4 and CDS lymphocytes (with a normal ratio between them), characterized by chronic candidiasis of the mucous membranes and skin, diarrhea, malabsorption due to malabsorption, pulmonary and other infectious processes, sepsis.

Adenosine deaminase (ADA) deficiency is inherited autosomal recessively. The genetic defect is caused by mutations within the gene on chromosome 20 that encodes ADA. The levels of T and B cells and immunoglobulins progressively decrease due to the accumulation of toxic metabolites (bATP and S-adenosylhomocysteine) that inhibit ribonucleotide reductase and, thus, DNA synthesis and cell proliferation. Immunological defects are associated with abnormalities of cartilage (ribs with expansion of their anterior part, disturbances in their connection with the vertebrae, thickening of the growth zones, shoulder blades, and pelvis). The diagnosis is made based on the detection of deoxyadenosine in the urine and the absence of the enzyme adenosine deaminase in erythrocyte lysates.

Purine nucleoside phosphorylase (PNP) deficiency is the result of a mutation in the gene located on chromosome 14 and responsible for the synthesis of this enzyme. The toxic metabolite, guanosine triphosphate (sPTP), accumulates as a result of enzyme deficiency and disrupts cell proliferation. T lymphocytes are more sensitive to SIGTF than B lymphocytes and are affected to a greater extent. This is the immunological difference between ADA and PNF deficiencies. Associated signs are: autoimmune hemolytic anemia and neurological symptoms in the form of seizures, spastic tetraplegia, ataxia.

Deficiency of MHC class II molecules (“bald lymphocyte syndrome”). This is a heterogeneous group of diseases (highlighted by at least, 3 subgroups), caused by a defect in proteins that trigger the transcription of class II molecules, as a result of which the function of antigen recognition with the participation of CD4+ lymphocytes is impaired. At the same time, the content of T and B cells is not significantly changed, but the subpopulation of T helper cells is reduced, cellular immunity and antibody synthesis are impaired. Immunological disorders are associated with developmental delay and persistent diarrhea.

Reticular dysgenesis is a rare disease inherited in an autosomal recessive manner. It results from impaired maturation of both lymphoid and myeloid progenitors (stem cell defect). The disease is characterized by pronounced lymphopenia, granulocytopenia, thrombocytopenia, and septicemia. infectious process With fatal in the first weeks of life.

Deficiency of CD3y or CD3e occurs with normal levels of T-, B-cells and immunoglobulins in the blood. Due to varying degrees expression of CD3 receptors on the T-cell membrane, the clinical manifestations of such deficiency are variable even within the same family.

Deficiency of CD8 lymphocytes is rare, inherited autosomal recessively, caused by a mutation of the gene located on chromosome 2, encoding protein kinase associated with the I^ chain of the T-cell receptor (ZAP70), and involved in signal transmission into the cell . The number of CD4+ cells is normal or increased, but they are functionally inactive, CD8+ cells are completely absent. The clinic is typical for SCID. Transplantation bone marrow in some children it led to correction of the deficiency.

X-linked lymphoproliferative syndrome (Duncan's disease) is a combined disorder of T- and B cell immunity, developing after infection with the Epstein-Barr virus. Before contact with this pathogen, there is no defect in the immune system, but after infection, which can occur at any age, hypogammaglobulinemia, a decrease in the synthesis of γ-interferon and the ratio of helper/suppressor cells, and the activity of natural killer cells develop. Cytotoxic T cells attack autologous T cells infected with the Epstein-Barr virus, which leads to severe mononucleosis with liver failure and death in 3/4 of cases.

Radiosensitive SCID was identified in 1998 and is characterized by impaired repair of DNA breaks that occur during recombination of immunoglobulin and TCR genes. Patients have impaired ak-

activity of DNA-dependent and other protein kinases, which are also responsible for the repair of DNA breaks induced by radiation. The gene is named Artemis.

As you know, immunity is the basis of health, because it is people with weakened immunity who constantly get sick. What is immunity? Immunity is resistance (and often successful if it is strong) to foreign organisms of various etiologies. These can be either viruses and bacteria, or invasions.

A child in the first days of life is extremely vulnerable, since his immunity is still underdeveloped. But already from the first months of life, the newborn begins to actively develop immunity, which helps fight pathogenic microorganisms. If the immune system is unable to protect the body from infections, then the newborn develops immunodeficiency, which is in some cases a very dangerous problem.

Severe combined immunodeficiency – what is it?

This disease is abbreviated as SCID. This disease is hereditary (that is, congenital, genetically transmitted from parents or other close relatives, or acquired due to a gene defect during fetal development), and therefore much more severe than acquired diseases. Moreover, it is very rare. SCID is characterized by impaired production or function of the most important cells of the immune system: T-lymphocytes and B-lymphocytes (they are produced in the thymus, which actively functions in children before puberty and in the bone marrow). T lymphocytes are responsible for cellular immunity, and B lymphocytes are responsible for the production of antibodies in the blood. Disruption of the functions of these lymphocytes entails a severe weakening of the immune system, so the patient “grabs” any virus or infection, which in a healthy person immediately dies thanks to the protection of the immune system, without causing the slightest symptoms. But in patients with combined immunodeficiency, these conditions cause not only severe severe symptoms, but also complications that can even threaten the life of the patient. Why combined? The word “combined” indicates that several types of leukocytes important for the immune system are involved in the process. In addition, SCID is a whole combination various diseases arising as a result of disturbances in the functioning of the immune system.

Types of SCID

The most common type of immunodeficiency (in 50% of patients this type is identified), characterized by a very scanty presence of T-lymphocytes and the absence of functions in B-lymphocytes. This condition is called X-linked severe combined immunodeficiency.
This is an immune disorder that is based on the accumulation in the body of substances that destroy mature B-lymphocytes and T-lymphocytes (especially the latter) - the condition is called adenosine deaminase deficiency.
The level of B lymphocytes decreases, and T lymphocytes, in turn, begin to function abnormally, which entails symptoms similar to autoimmune reaction(when the immune system begins to destroy the cells of the body itself) – Omenn syndrome.
There are other types of SCID. For example, sometimes the body experiences a deficiency of other types of leukocytes - monocytes, neutrophils, etc.

Causes of SCID

The cause of the disease usually lies in a genetic defect (more than 15 variations of such defects are known). The disease follows abnormalities in the different chromosomes on which the genes are located. Whatever defect causes this disease, clinical picture his is the same. We will look at it below.

SCID symptoms

Symptoms that occur in patients in the first year of life:

Frequent diseases (viral, fungal or antibacterial) of the skin and mucous membranes internal organs
From the gastrointestinal tract, diarrhea and malabsorption syndrome are observed (this is a violation of the absorption of nutrients into the intestines)
Pneumonia
Meningitis
Sepsis (i.e. blood poisoning).

Other symptoms:

Diseases after contact with non-pathogenic (i.e. not causing diseases in healthy people) bacteria
Fungal diseases
Lack of appetite
Fever
Diseases after vaccination (there should not be such a reaction)
Complications after BCG (vaccination to prevent tuberculosis), which are manifested by the appearance of ulcers and purulent inflammation on the body at the injection site.
Retarded physical and motor development (conscious movements).

The main symptom that manifests itself in children under 1 year of age is frequent diseases (both fungal, viral and antibacterial). If someone from the family of both parents has encountered something similar, then the child should be examined in case of a severe course of some inflammatory process to exclude the possibility of SCID.

Diagnosis of the disease

Examination of the patient by a doctor (usually referred to an infectious disease specialist or immunologist). In this case, patients are diagnosed with: underdevelopment of lymphoid tissue, skin infections (oral ulcers), rash, changes in the lungs (determined using special device), manifestation of complications after BCG. In this case, it is advisable to carry out the following examinations:

A general blood test that reveals lymphopenia (that is, a decrease in the white blood cell count) in patients.
Immune status: blood is taken from a vein to find out the number of T-lymphocytes, B-lymphocytes, NK-lymphocytes (these are components of the immune system).
Genotyping - determining the presence (or absence) of genetic defects, since they are the cause of the disease.
Pretanal diagnosis is done when the mother has already given birth to a patient with SCID, since the diagnosis can be repeated in subsequent pregnancies. The chorionic villi are examined to determine the possibility of repeating the diagnosis.
A therapist wouldn't hurt either.

Treatment of SCID

Treatment must be started immediately. The following activities are carried out:

Active therapy - antibacterial, antifungal, antiviral, since patients develop numerous diseases due to weak immunity
Administration of injections containing immunoglobulins that increase the body's resistance
Sometimes transfusion of individual blood components
Bone marrow transplant (from an unrelated or related donor)
Cord blood transplant (from an unrelated or related donor)
Correction of genetic disorders is still under development. /li>

The most common operation of all of the above is bone marrow transplantation (usually from a close relative).

Forecast

If treatment is started on time (in particular, patients should receive a bone marrow transplant as soon as possible), then the percentage of recoveries is quite high.

Prevention

If there is a suspicion of severe combined immunodeficiency, then it is necessary to perform surgery as soon as possible, and until then keep the patient in a sterile box. Contact with other people is not allowed. It is also necessary to exclude vaccinations. Antibiotics are taken to prevent Pneumocystis pneumonia, which occurs only in severe combined immunodeficiency. During pregnancy, it is advisable for the expectant mother to do a chorionic villus analysis if one of her relatives has already encountered this.

Catad_tema Pathology of the immune system - articles

Severe combined immune deficiency in children

ICD 10: D81

Year of approval (revision frequency): 2016 (reviewed every 3 years)

ID: KR335

Professional associations:

National Society of Pediatric Hematology and Oncology
National Society of Experts on Primary Immunodeficiencies

Approved

National Society of Pediatric Hematologists and Oncologists

Agreed

Scientific Council of the Ministry of Health Russian Federation __ __________201_

Severe combined immune deficiency

Pneumocystis pneumonia

Maternal chimerism

Prenatal diagnosis

Hematopoietic stem cell transplantation

Intravenous immunoglobulin

List of abbreviations

ADA - adenosine deaminase

ADP - adenosine diphosphate

ALT - alanine aminotransferase

AR - autosomal recessive type of inheritance

AST - aspartate aminotransferase

ATG - antithymocyte globulin

ACD - anemia of chronic diseases

BCG - bacillus Calmette-Guerin

IVIG - intravenous immunoglobulins

GCS - glucocorticosteroids

G-CSF - granulocyte colony-stimulating factor

DNA - deoxyribonucleic acid

Gastrointestinal tract - gastrointestinal tract

IG - immunoglobulin

CIN - combined immune deficiency

BM - bone marrow

CT - computed tomography

Health care facility - medical and preventive institution

MOH - Ministry of Health

ICD-10 - International Classification of Diseases, 10th Revision

MRI - magnetic resonance imaging

PNP - purine nucleoside phosphorylase

PCR - polymerase chain reaction

RCT - randomized controlled trials

RNA - ribonucleic acid

GVHD - graft versus host disease

RF - Russian Federation

DDS - DiGeorge syndrome

USA – United States of America

HSCT - hematopoietic stem cell transplantation

SCID - severe combined immune deficiency

Ultrasound - ultrasound examination

FSCC DGOI - Federal scientific and clinical center pediatric hematology, oncology and immunology

XС - X-linked type of inheritance

CVC - central venous catheter

CNS - central nervous system

ECG - electrocardiography

ADA - adenosine deaminase

CD - cluster of differentiation

CRP - C-reactive protein

eADA - erythrocyte adenosine deaminase

EBV - Epstein-Barre visrus - Epstein-Barr virus

GPPs - good practice points

HLA – human leukocyte antigens – human histocompatibility antigens

IL - interleukin

IUIS – International Union of Immunological Societies - International Union

immunological societies

NGS – next generation sequencing - next generation sequencing

PNP - purine-nucleoside phosphorylase - purine nucleoside phosphorylase

SIGN 50 - Scottish Intercollegiate Guidelines Network

TAP - transporter associated protein

WHN - winged helix nude С

ZAP - zeta associated protein

Terms and Definitions

Intravenous immunoglobulins – preparations containing predominantly normal human IgG. They are made from pooled plasma of thousands of healthy donors, using special purification and virus inactivation methods.

Polymerase chain reaction- a method of molecular biology that allows you to amplify (multiply) a specific section of DNA

Sequencing DNA - determination of its nucleotide sequence. As a result of sequencing, a description of the primary structure of linear DNA is obtained in the form of a nucleotide sequence in text form.

Hematopoietic stem cell transplantation – a method of treating some hereditary and acquired hematological, oncological and immune diseases, based on replacing the patient’s own pathological hematopoiesis with the normal hematopoiesis of the donor.

Autosomal recessive type of inheritance – inheritance of gene mutations, when for the disease to manifest, a mutation of a gene localized in the autosome must be inherited from both parents. The mutation appears only in the homozygous state, that is, when both copies of the gene located on homologous autosomes are damaged. If the mutation is in a heterozygous state, and the mutant allele is accompanied by a normal functional allele, then the autosomal recessive mutation does not manifest itself (carriage).

X-linked type of inheritance– inheritance of mutations of genes located on the X chromosome. In this case, females are usually asymptomatic carriers, and only males suffer from the disease.

TREC– circular DNA fragments formed during the development of T lymphocytes in the thymus, in particular, during the formation of the T cell receptor. Their concentration in the blood reflects the effectiveness of thymopoiesis. Used to screen for T cell immunodeficiencies.

1. Brief information

1.1 Definition

Severe combined immune deficiency (SCID) is a genetically determined (primary) immunodeficiency characterized by the almost complete absence of mature T-lymphocytes in the presence or absence of B- and NK-lymphocytes, which leads to early, extremely severe infections of viral, bacterial and opportunistic nature and, in the absence of pathogenetic therapy, death in the first two years of life.

1.2 Etiology and pathogenesis

SCID is caused by mutations in various genes responsible for the maturation and function primarily of T lymphocytes, and in some cases, other subpopulations of lymphocytes. Currently, the genetic nature of more than 15 forms of SCID is known (Table 3), some patients have still not verified genetic defects. The disease can be inherited either X-linked (in about a quarter of cases) or autosomal recessively. The estimated frequency of certain genetic defects, calculated based on data from perinatal screening for SCID in the United States, is presented in Fig. 1.

Figure 1. Frequency of detection of various defects in SCID.

As is known, T lymphocytes are the main effector and regulatory cells specific immunity. In their absence, the functions of antimicrobial and antiviral immunity suffer, and the formation of self-tolerance is disrupted. Even in cases where B lymphocytes are present in patients, the function of specific antibody formation also suffers significantly, since its implementation requires interaction between T and B lymphocytes.

1.3 Epidemiology

The birth rate of patients with SCID is 1:58,000 newborns (1:46,000-1:80,000); males predominate among patients.

1.4 Coding according to ICD-10

Combined immunodeficiencies(D81):

D81.0 - Severe combined immunodeficiency with reticular dysgenesis;

D81.1 - Severe combined immunodeficiency with low levels of T and B cells;

D81.2 - Severe combined immunodeficiency with low or normal B-cell counts;

D81.3 - Adenosine deaminase deficiency;

D81.4 - Nezeloff syndrome;

D81.5 - Purine nucleoside phosphorylase deficiency;

D81.6 - Deficiency of class I molecules of the major histocompatibility complex;

D81.7 - Deficiency of class II molecules of the major histocompatibility complex;

D81.8 - Other combined immunodeficiencies;

D81.9 - Combined immunodeficiency, unspecified.

1.5 Classification

According to the 2015 classification of PIDS, approved by the International Union of Immunological Societies (IUIS), there are 2 groups of SCID, depending on the presence or absence of B-lymphocytes: T-B- and T-B+. These two large groups can also be divided into subgroups depending on the presence or absence of NK cells: T-B-NK+, T-B-NK-, T-B+NK+, T-B+NK- (Table 1).

The clinical picture of the disease is practically independent of the genetic form of SCID.

Combined immunodeficiency	inheritance	Clinical features	Circulating lymphocytes
Combined immunodeficiency	inheritance	Clinical features
T-V+ TKIN
Shortage?-chains
JAK3 deficiency
IL7R deficiency?
CD45 deficiency		Normal gd T cells
CD3d deficiency		Lack of gd T cells
CD3e deficiency		Lack of gd T cells
CD3z deficiency		Lack of gd T cells
Coronin1A deficiency		EBV-associated lymphoproliferation
DOCK2 deficiency		Decreased NK cell function
T-V-TKIN
AK2 deficiency (Reticular dysgenesis)		Granulocytopenia, thrombocytopenia, deafness
RAG1 deficiency		Violation of VDJ recombination
RAG2 deficiency		Violation of VDJ recombination
Deficiency of DNA PKCs		Autoimmunity, granulomas
DCLRE1C(Artemis) deficiency		Increased sensitivity to radiation
Cernunnos deficiency		Radiation sensitivity, microcephaly, developmental delay
DNA lyase IV deficiency		Radiation sensitivity, microcephaly, developmental delay
ADA Deficiency		Expansion of osteochondral joints, neurological symptoms, hearing impairment

Table 1. Type of inheritance and immunological disorders in the main forms of severe combined immune deficiency

2. Diagnostics

Consensus European Society immunodeficiencies (ESID), a combination of signs is required to confirm the diagnosis of SCID:

one of the following: invasive bacterial, viral, fungal or opportunistic infections; prolonged diarrhea with retarded physical development; family history of SCID;
onset of symptoms at 1 year of life;
exclusion of HIV infection;
two of the following criteria: significantly reduced/absent CD3+ or CD4+ or CD8+ lymphocytes; reduced naïve CD4+ and/or CD8+ lymphocytes; increased g/d T lymphocytes; significantly reduced/absent proliferation in response to mitogens or TCR stimulation.

2.1 Complaints and anamnesis

The patient's parents usually complain about loose stools that appeared in the first months of life, lack of weight gain, difficult-to-treat diaper dermatitis and oral thrush. Sometimes parents report one or more severe infections (pneumonia, sepsis), but often the first respiratory infection is so severe that it suggests immunological deficiency.

When collecting a family history, one should pay attention to cases of repeated severe infections and deaths of children at an early age with clinical signs infectious diseases. The death of boys in several generations in the family suggests an X-linked nature of the disease. Consanguineous marriage among parents increases the likelihood of an autosomal recessive pathology.

When interviewing parents, it is necessary to clarify the characteristics of the child’s physical development, weight gain, timing of occurrence, frequency and severity of infectious diseases (diarrhea, fungal infections of the skin and mucous membranes, pneumonia and infections of other localizations). It is also necessary to find out whether BCG vaccination was carried out in the maternity hospital, whether changes were noted at the site of BCG vaccination and regional lymph nodes 3-4 months after vaccination.

2.2 Physical examination

Patients with SCID usually lose weight from the first months of life. Patients with SCID often experience “unmotivated” low-grade fevers and fever without an obvious source of infection at the time of presentation. However, the opposite situation often occurs - the absence of a temperature response to a severe, generalized infection.

It is important to pay attention to the presence of candidiasis of the skin and mucous membranes, the presence of maceration of the perianal area (due to chronic diarrhea). In the case of previous transfusion of non-irradiated red blood cells to patients or during the engraftment of maternal lymphocytes (maternal chimerism), a maculopapular polymorphic rash is possible, indicating the presence of graft-versus-host disease. Needs to be inspected left shoulder at the site of BCG vaccination to exclude local BCGitis and others skin for infiltrative polymorphic elements (generalized BCGit).

In general, SCID patients are characterized by hypoplasia of peripheral lymphoid tissue, but in the case of BCGitis, left axillary lymphadenopathy may be observed.

Pneumonia in SCID often has an etiology of P.carinii. As is known, such pneumonia is accompanied by progressive respiratory failure with tachypnea, decreased oxygen saturation, and an abundance of crepitant wheezing.

Liver enlargement is often noted as a manifestation of toxic hepatitis with defects in purine metabolism, hepatic GVHD.

2.3 Laboratory diagnostics

Comments:Patients with SCID often have lymphopenia and may experience anemia of chronic inflammation.

It is recommended to determine biochemical blood parameters (urea, creatinine, bilirubin fractions, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase), as well as partial pressure of oxygen (pO2).

Comments:Determined to assess organ damage.

A study of serum immunoglobulin levels is recommended.

Comments: In most cases, hypogammaglobulinemia is detected in patients with SCID from the first months of life. However, given the low age standards in children of the first year of life, assessment of the level of immunoglobulins is often uninformative in making a diagnosis of SCID. We should also not forget that high levels of IgG in the first months of life are due to the persistence of maternal immunoglobulin obtained transplacentally and can occur in infants with SCID. Even with normal concentrations of immunoglobulins in SCID, their specificity suffers significantly, which can be determined by the low titer of post-vaccination antibodies in the case of child vaccination.

Phenotyping of lymphocyte subpopulations is recommended.

Comments:During phenotyping, a significant decrease in T lymphocytes occurs in all forms of SCID, but the number of B lymphocytes and NK cells depends on the genetic defect underlying SCID.

Also, a normal or close to normal number of T lymphocytes is observed with maternal chimerism. These lymphocytes have a memory cell phenotype CD3+CD4+CD45RO+.

All variants of SCID are characterized by a significant decrease in the proliferative activity of lymphocytes.

A TREC study (T cell excision circles) is recommended.

Comments:TREC are a measure of the efficiency of T lymphocyte production in the thymus. TREC concentrations are significantly reduced in all types of SCID, regardless of the genetic defect.

Molecular genetic research of the relevant genes is recommended.

Comments:The clinical and laboratory picture is usually sufficient to confirm the diagnosis of SCID. Due to the need for immediate stem cell transplantation in SCID, genetic confirmation of the diagnosis is not required for its implementation, but is necessary for family counseling. Identification of causative gene mutations is carried out using polymerase chain reaction and subsequent sequencing of the resulting products or using next generation sequencing (NGS) methods, followed by confirmation of the defect using PCR. Usually they start with the study of the IL2RG gene in males, if its sequence is normal and/or the patient is female - all other genes, depending on the patient’s immunophenotype and the frequency of occurrence of the defect (NGS panels can be used).

In cases of suspicious symptoms, it is necessary to exclude deletion of the short arm of chromosome 22 (DiGeorge syndrome) using the FISH method.

Microbiological and virological studies are recommended.

Comments: Serological tests in patients with SCID are not informative and should not be used. The virological status of the patient is characterized by quantitative (preferably) or qualitative determination of viruses using the polymerase chain reaction (PCR) method in blood, feces, cerebrospinal fluid, broncho-alveolar lavage, and biopsy material. It must be remembered that the absence of viremia is not evidence of a negative virological status; it is necessary to study the appropriate media in case of damage to certain organs (up to a biopsy). Cultures of biomaterial (for flora and fungi) with determination of antibiotic sensitivity from mucous membranes, from foci of infection (including blood and urine cultures for appropriate symptoms), as well as stool cultures, bronchoalveolar lavage, cerebrospinal fluid and biopsy material should always be carried out in the presence of infectious foci.

HLA typing is recommended

Comments:Since prompt hematopoietic stem cell transplantation (HSCT) for SCID is the only condition for preserving the life of these patients, HLA typing with siblings, parents (in the absence of siblings), or typing to find an unrelated donor should be carried out immediately after the diagnosis of SCID.

2.4 Instrumental diagnostics

Computed tomography of the lungs is necessary to assess damage to this organ. The interstitial lung lesions characteristic of SCID cannot be fully assessed by chest radiography, so a CT scan of the lungs should be performed even if the radiograph is normal.

All patients are recommended to undergo ultrasound examination abdominal cavity and retroperitoneal space to assess the involvement of internal organs.

Other instrumental studies carried out in the presence of appropriate clinical indications.

2.5 Other diagnostics

Due to frequent viral eye infections in patients with SCID, an examination by an ophthalmologist, including a slit lamp, is necessary. If the lungs are affected, broncho-alveolar lavage is performed, if the central nervous system is affected, a lumbar puncture is performed, followed by microbiological and virological examination of the media.

Differential diagnosis should primarily be made with:

? manifestations of HIV infection;

? other (syndromic) combined immunodeficiencies, primarily DiGeorge syndrome (which is characterized by a combination of varying degrees of severity of symptoms: structural features of the facial skeleton, morphology ears, decoupling of the hard and soft palate, hypocalcemia due to malnutrition parathyroid glands, conotruncal malformations of the heart, other developmental defects, mental retardation);

? septic condition, in which transient deep lymphopenia is often noted;

? defects of the lymphatic vessels, primarily intestinal lymphangiectsia, in which lymphopenia, hypogammaglobulinemia and hypoalbuminemia are often ignored.

3. Treatment

3.1 Conservative treatment

Goal of treatment: stabilization of the condition and prevention of new infectious episodes during the period of preparation for HSCT.

Immediately after the diagnosis of SCID, it is recommended that the child be kept in gnotobiological conditions (sterile box).

Comments:SCID are emergency in pediatrics.

Saving is not recommended breastfeeding due to the risk of infection, primarily CMV, and also due to increased diarrhea syndrome when using lactose-containing products. Recommended artificial feeding, based on hydrolyzed mixtures, dairy-free cereals and other age-appropriate products that have undergone thorough heat treatment.

In the absence of infectious foci, continuous preventive antimicrobial therapy with the drug is recommended wide range, antifungal - fluconazole (when receiving cultures - according to sensitivity), prevention of Pneumocystis infection with co-trimoxazole (prophylactic dose 5 mg/kg, therapeutic dose 20 mg/kg of co-trimoxazole intravenously), prevention of CMV infection with ganciclovir.

Comments:Since in Russia BCG vaccination is carried out in the first days of life, children with SCID in most cases become infected, and they develop BCG-itis of varying severity (from local to generalized infection). BCG infection requires long-term intensive therapy with at least 3 antimycobacterial drugs. In case of infection, intensive antimicrobial, antiviral and antifungal therapy is carried out according to sensitivity.

If there are symptoms of GVHD and/or immune damage to organs, immunosuppressive therapy with glucocorticosteroids and other immunosuppressive drugs is recommended - individually.

If transfusions of blood components (erythrocyte mass, platelet concentrate) are necessary, it is recommended to use only irradiated and filtered drugs. In case of transfusion of non-irradiated erythrocytes and platelets, post-transfusion GVHD develops.

Due to massive immune damage to organs, immunosuppressive therapy in the form of glucocorticosteroids (GCS) 1-1.5 g/kg body weight is recommended until HSCT. In case of incomplete effect and/or development of significant side effects from GCS therapy, therapy with anti-thymocyte immunogloblin at a dose of 10 mg/kg for 3 days is recommended.

Recommended preventive treatment using intravenous immunoglobulin transfusion (IVIG) from the moment of diagnosis until the restoration of immune function after HSCT, since all patients with OM, regardless of the level of serum immunoglobulins, have impaired antibody production.

Comments: In patients with OM, treatment is carried out weekly at a dose of 400–600 mg/kg. For the treatment of severe infections, IVIG is used at a dose of 1 g/kg, for the treatment of septic conditions - IVIG enriched with IgM (normal human immunoglobulin) at a dose of 3 ml/kg per day for 2-5 injections.

3.2 Hematopoietic stem cell transplantation

The goal of treatment is to save the patient's life.

HSCT is recommended for all SCID patients

Comments: If SCID is diagnosed during the first month of life, before the onset of infectious complications, adequate therapy and allogeneic HLA identical or haploidentical stem cell transplantation (HSCT) ensures survival in more than 90% of patients, regardless of the form of immunodeficiency. In case of later diagnosis, severe infections develop that are difficult to treat, and patient survival rate drops sharply - to 40-50%. In any case, HSCT is the only curative treatment method for patients with SCID; without HSCT, mortality is 100% in the first 12-18 months of life.

It is carried out from a related compatible, unrelated compatible or haploidentical donor according to the methods used in a specific center. Depending on the infection status and developed complications, the presence and intensity of conditioning is determined. In the absence of a compatible related donor, the results of haplotransplantation are comparable to the results of an unrelated transplantation from a fully compatible donor, but haplotransplantation is possible in as soon as possible Therefore, if the patient's condition is unstable, transplantation from the parents is preferable.

3.3 Surgical treatment

It is carried out according to indications, depending on complications.

3.4 Gene therapy

Active clinical trials are currently underway that will enable the routine use of gene therapy for some forms of SCID.

4. Rehabilitation

From the moment of diagnosis until the start of restoration of immune function after HSCT, the patient should be in a hospital specializing in the management of patients with SCID.

5. Prevention and clinical observation

Preventive measures include medical genetic counseling of families and prenatal diagnosis, which is carried out using a molecular genetic study of chorionic villus sampling to identify mutations in the corresponding gene, which helps prevent the birth of other patients with this disease in SCID families.

Prenatal diagnosis is necessary for all subsequent pregnancies of the mother in this marriage and in other marriages with an X-linked type of inheritance. With an X-linked type of inheritance, it is necessary to test for carriage of the mutation the patient's sisters, all sisters of the mother of childbearing age, and, if indicated, other female relatives.

Prenatal diagnosis is indicated only in consanguineous marriages. In other cases, the risk of the disease in the patient's children is less than 0.1%. All children of a patient with an autosomal recessive type of inheritance and all daughters of a patient with an X-linked type of inheritance are carriers of the mutated gene; they need family counseling.

6. Additional information affecting the course and outcome of the disease

With successful HSCT, the prognosis for quality and life expectancy is generally favorable; it is largely determined by the severity of chronic foci of infection and organ damage that have formed at the time of transplantation. Average duration The life expectancy of SCID patients without HSCT is currently 7 months.

Criteria for assessing the quality of medical care

Quality criterion	Meaning
The need for urgent medical measures was assessed ( artificial ventilation lungs)
A clinical blood test, biochemical blood test, clinical urine test, coagulogram, determination of infection with HIV, hepatitis B and C viruses, ECG, abdominal ultrasound, chest radiography were performed
Determination of serum immunoglobulins, specific post-vaccination antibodies, phenotyping of blood lymphocytes was carried out
Was a virological study performed to exclude viral damage to organs using the PCR method (taking into account immunodeficiency and the lack of information content of serological examination methods)?
A molecular genetic study of potentially affected genes was performed
Conducted replacement therapy intravenous immunoglobulin preparations, regardless of the level of immunoglobulin G
The patient and his family are informed about the need for stem cell transplantation to cure the disease
Family genetic counseling of the patient was carried out

Bibliography

Appendix A1. Composition of the working group

Balashov Dmitry Nikolaevich- Doctor of Medical Sciences, member National Society experts in the field of primary immunodeficiencies, member of the National Society of Pediatric Hematologists and Oncologists, member of the European Society of Immunodeficiencies

Rumyantsev Alexander Grigorievich - Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Medical Sciences, President of the National Society of Experts in the Field of Primary Immunodeficiencies, Member of the National Society of Pediatric Hematologists and Oncologists, Member of the European Society of Hematologists

Shcherbina Anna Yurievna- Doctor of Medical Sciences, Executive Director National Society of Experts in the Field of Primary Immunodeficiencies, member of the National Society of Pediatric Hematologists and Oncologists, member of the European Society of Immunodeficiencies

Conflict of interest: Sherbina A.Yu. over the past 5 years, she has been lecturing with the support of the companies CSL Behring, Kedrion, Biotest, RFarm, which are manufacturers\distributors of intravenous immunoglobulin preparations.

Hematologists 01/14/21;

Immunologists 03/14/09;

Pediatricians 01/14/08;

General practitioners 08/31/54.

Table P1– Levels of evidence

Confidence level	Source of evidence
	Prospective randomized controlled trials A sufficient number of adequately powered studies involving large quantity patients and obtaining a large amount of data Large meta-analyses At least one well-designed randomized controlled trial Representative sample of patients
	Prospective with or without randomization with limited data Several studies with small numbers of patients Well-designed prospective cohort study Meta-analyses are limited but well conducted Results are not representative of the target population Well-designed case-control studies
	Non-randomized controlled trials Insufficiently controlled studies Randomized clinical trials with at least 1 major or at least 3 minor methodological errors Retrospective or observational studies Series of clinical observations Conflicting data that does not allow a final recommendation to be made
	Expert opinion/data from the expert commission report, experimentally confirmed and theoretically substantiated

Table P2– Recommendation strength levels

Level of persuasiveness	Description	Decoding
		First line method/therapy; or in combination with standard technique/therapy
		Method/therapy second line; or in case of refusal, contraindication, or ineffectiveness of a standard technique/therapy. Monitoring for adverse events is recommended
	there is no convincing evidence of either benefit or risk)	There are no objections to this method/therapy or no objections to the continuation of this method/therapy
	Absence of convincing level I, II or III publications showing a significant superiority of benefit over risk, or convincing publications of I, II or III level of evidence showing a significant superiority of risk over benefit

Appendix B: Patient Information

Severe combined immune deficiency (SCID) is a genetically determined disease, which is based on a severe defect of the immune system. The disease is characterized by severe viral and bacterial infections and, in the absence of stem cell transplantation, death in the first two years of life.

SCID is caused by defects (mutations) in various genes responsible for the maturation and function primarily of T lymphocytes, and in some cases, other subpopulations of lymphocytes. Currently, the genetic nature of more than 15 forms of SCID is known; some patients have genetic defects that have not yet been verified. Patients with SCID are characterized by an early (in the first weeks or months of life) onset of clinical manifestations of the disease in the form of loose stools, persistent thrush, diaper dermatitis, and severe infections. If a child is vaccinated with BCG in the maternity hospital or later, the development of regional and/or generalized BCG infection is typical.

Against the background of severe infections, there is a lag in physical and motor development. It should be remembered that even with SCID, infants do not immediately develop all of the above symptoms and may grow and develop normally within a few months. Transplacental transfer of maternal lymphocytes can cause symptoms of graft-versus-host disease (GVHD), referred to as maternal-fetal GVHD. It manifests itself mainly in the form skin rash and/or damage to the liver and intestines.

HSCT is the only way to save the patient's life. HSCT is performed from a compatible brother/sister, or, in their absence, from an unrelated compatible donor or from parents. The outcomes of HSCT depend largely on the existing infectious status, damage to organs and systems.

The risk of having other children with SCID in this family is approximately 25%. It is recommended to conduct family counseling and prenatal/preimplantation diagnostics to exclude the birth of other children with this disease.

Severe combined immunodeficiency is characterized by the absence of T lymphocytes and low, high, or normal numbers of B lymphocytes and natural killer cells. Most infants develop opportunistic infections within 1 to 3 months of life. When making a diagnosis, lymphopenia, the absence or very low number of T lymphocytes, and impaired lymphocyte proliferation when exposed to a mitogen are important. Patients must be in a protected environment; The only treatment is bone marrow stem cell transplantation.

Severe combined immunodeficiency (SCID) results from mutations in at least 10 different genes, which manifest in 4 forms of the disease. In all forms, T-lymphocytes are absent (T-); but depending on the form of severe combined immunodeficiency, the number of B lymphocytes and natural killer cells may be low or absent (B-, NK-), or normal or high (B+, NK+). But even if the level of B lymphocytes is normal, due to the lack of T lymphocytes they cannot function normally. The most common type of inheritance is X-linked inheritance. In this form, there is no y-chain in the protein molecule of the IL2 receptor (this chain is a component of at least 6 cytokine receptors); this is the most severe form with the T-, B+, NK- phenotype. Other forms are inherited in an autosomal recessive manner. The two most common forms result from deficiency of ADA adenosine deaminase, which leads to apoptosis of B, T, and natural killer cell precursors; the phenotype of this form is T-, B-, NK-. In another form, there is a deficiency of the a-chain in the protein molecule of the IL7 receptor; the phenotype of this form is T-, B+, NK+.

Most children with severe combined immunodeficiency develop candidiasis, pneumonia, and diarrhea by 6 months, leading to developmental disorders. Many people develop graft-versus-host disease after receiving maternal lymphocytes or blood transfusions. Other patients live up to 6-12 months. Exfoliative dermatitis may develop as part of Omenn's syndrome. ADA deficiency can lead to bone abnormalities.

Treatment of severe combined immunodeficiency

Diagnosis is based on lymphopenia, low count or complete absence T-lymphocytes, lack of proliferation of lymphocytes in response to stimulation with mitogen, lack of X-ray shadow of the thymus, impaired development of lymphoid tissue.

All forms of severe combined immunodeficiency are fatal if not diagnosed and treated early. Additional treatment methods may include the administration of immunoglobulin and antibiotics, including prophylaxis Pneumocystis jiroveci (previously P. carinii). 90-100% of patients with severe combined immunodeficiency and its forms are indicated for bone marrow stem cell transplantation from an HLA-identical, mixed leukocyte culture-matched sibling. If it is not possible to select an HLA-identical sibling, haploidentical bone marrow from one of the parents with carefully washed T-lymphocytes is used. If severe combined immunodeficiency is diagnosed before 3 months of age, the survival rate after bone marrow transplantation by any of these methods is 95%. Preimplantation chemotherapy is not performed because the recipient does not have T lymphocytes, and therefore graft rejection is not possible. Patients with ADA deficiency who are not candidates for bone marrow transplantation are given polyethylene glycol, a modified bovine ADA, once or twice a week. Gene therapy is successful in X-linked severe combined immunodeficiency but can cause T-cell leukemia, limiting its use.