Pediatric ataxia telangiectasia syndrome


Introduction to pediatric ataxia telangiectasia syndrome

Ataxia telangiectasia syndrome is a group of multi-systemic autosomal recessive hereditary diseases, also known as LouisBar syndrome. The main clinical features are cerebellar syndrome and facial skin, conjunctival telangiectasia; Ionizing radiation is sensitive, T cell function is defective, and repeated respiratory infections are prone to occur.

basic knowledge

The proportion of illness: 0.002%

Susceptible people: children

Mode of infection: non-infectious

Complications: bronchiectasis, diabetes


Pediatric ataxia telangiectasia syndrome etiology

(1) Causes of the disease

The disease (ataxia telangiectasia mutated, ATM) gene is located on chromosome 11q22~23 and contains 66 exons. From amino to carbon, it can be divided into ATM, open reading frame (ORF) and phospholipid inositol 3-kinase. Three regions (phosphatidylinositol 3-kinases, PI3-kinase).

There are extensive mutation sites in the untranslated regions (UTRs) of the ATM gene, involving three regions of ATM, ORF and PI-3 kinase, and 70% of ATM gene mutations causing ATM protein inactivation are large fragment deletions, other mutations. The form has insertions caused by blocking splicing, deletions within the framework and nonsense mutations.

(two) pathogenesis

As a PI3-kinase related family, ATM protein is involved in cell cycle regulation, intracellular protein transport and DNA damage. When cells are exposed to radiation, the main function of ATM protein is to make the cell cycle in a stationary phase, so that the damaged DNA has The opportunity is restored, ATM maintains the stability of p53 through phosphorylation pathway and binds to the protein tyrosine kinase c-Abl to regulate the cell cycle. The ATM gene mutation keeps the damaged cells in the dividing phase, and the damaged DNA is in During the process of cell division, the DNA is not repaired, it is more prone to further rupture, and the telomere is shortened, leading to apoptosis, which may explain the high sensitivity of patients with ataxia telangiectasia syndrome. Progressive cerebellar ataxia induced by cerebellum Purkinje cell death.

According to the principle of null alleles, different forms of mutation can lead to great differences in clinical phenotype, from the typical ATS clinical phenotype to no clinical symptoms.


Pediatric ataxia telangiectasia syndrome prevention

1. Genetic counseling and family survey

Although most diseases cannot determine the genetic pattern, genetic counseling for diseases with defined genetic patterns is valuable if genetically immunodeficiency in adults will provide the developmental risk of their children; if a child has autosomals Recessive genetic or sexually linked immunodeficiency disease, it is necessary to tell parents that their next child is likely to be sick, for patients with antibodies or complement deficiency patients should check the antibody and complement levels to determine the family disease For some diseases that can be genetically mapped, such as chronic granulomatosis, parents, siblings and their children should be genetically tested. If a patient is found, it should also be performed among his or her family members. Check that the child's child should be carefully observed at the beginning of the birth for any disease.

2. Prenatal diagnosis

Some immunodeficiency diseases can be prenatally diagnosed, such as cultured amniotic fluid cell enzymology can diagnose adenosine deaminase deficiency, nucleoside phosphorylase deficiency and some combined immunodeficiency diseases; fetal blood cell immunological test can be Diagnosis of CGD, X-linked no-gammaglobulinemia, severe combined immunodeficiency disease, thereby terminating pregnancy, preventing the birth of children, early accurate diagnosis of ataxia telangiectasia syndrome, early specific treatment and genetics Consultation (prenatal diagnosis or even intrauterine treatment) is very important.


Complications of pediatric ataxia telangiectasia syndrome Complications, bronchiectasis, diabetes

Can cause severe dyskinesia, mental retardation; often complicated by viral or bacterial infections, repeated pulmonary infections can lead to chronic bronchiectasis; can be combined with insulin-resistant diabetes and malignant tumors.


Pediatric ataxia telangiectasia syndrome symptoms common symptoms repeated infection mental retardation immune deficiency ataxia bacterial infection watching rapid movement... diabetes testicular atrophy

1. Neurological performance

Ataxia occurs in 20% of those within 1 year old, 65% of 2 years old, 85% of 4 years old, and a few cases can be delayed until 4 to 5 years old. The disease progresses slowly, but it is progressive, eventually leading to severe dyskinesia. The typical performance is that when the patient looks at a fast moving object, the head rotates faster than the eye movement. In some cases, mental retardation occurs, but most patients have normal intelligence and vital functions before the age of 20 or 30.

2. Eye and skin telangiectasia

Capillary vasodilation occurs in the ball-bound membrane at the earliest age of 1 to 6 years. With age, telangiectasia is more pronounced and occurs in other areas, such as the nasal side, ears, posterior forearm and leg flexion, and the back of the hand and foot.

3. Repeated infection

Repeated pulmonary infection can lead to chronic bronchiectasis, which can occur before ataxia and telangiectasia, and patients are prone to concurrent viral or bacterial infections, but unlike other immunodeficiency diseases, ATS patients rarely have opportunistic infections.

4. Endocrine abnormalities

ATS patients who survive to adolescence may have no secondary sexual characteristics. Some male patients have testicular and female ovarian atrophy, and may grow with stagnation as the disease progresses. They may have anti-insulin diabetes due to insufficient insulin receptor or affinity. Attenuated, it has recently been found that ATM mutations affect glucose intracellular signaling in the PI3-kinase pathway and are responsible for insulin-resistant diabetes.

5. Malignant tumor

The incidence of cancer in patients with ATS (homozygous) is about 100 times higher than that of healthy people of the same age. The most common tumors are lymphoid proliferative malignancies, others include adenocarcinoma, germblastoma, reticuloma and myeloma. Neurological malignancies, atypical cases and mild patients have late symptoms, slow clinical progression, and reduced radiosensitivity.


Examination of pediatric ataxia telangiectasia syndrome

Cytological examination

Peripheral blood cell counts often show lymphopenia and erythrocytosis, granulocytes can also be reduced, cytological findings show chromosomal instability and significant rupture, shortened lifespan of cultured lymphocytes in vitro, highly sensitive to radiation and chemical radiation, cell cycle G1 In the S phase, there is a lack of cut-points, so that the cells can not stay in the quiescent phase. The p53 protein is increased after normal human lymphocytes are treated by radiation, which delays the cell cycle from G1 to S phase, and there is a barrier to the p53 protein signaling pathway in AT patients. The cell cycle cannot be delayed afterwards.

2. Humoral immunodeficiency

80% of cases have IgA deficiency, serum IgE deficiency is also more common, IgG reduction is rare, but often accompanied by IgG2 and IgG2/IgG4 subtype deficiency, 80% of cases have low molecular weight IgM in serum, antibody response to viral and bacterial antigens Obviously lacking, the reason for the low function of immunoglobulins and antibodies is B cell differentiation dysfunction, which may be endogenous defects of B cells, such as chromosome breaks, translocation and abnormal rearrangement of chromosomes 7 and 14 encoding Ig gene. It may also be caused by the lack of help of T cells to B cells, such as T cell receptor gene recombination disorders, etc. In addition, the production of anti-Ig autoantibodies may also be a factor of Ig decline.

3. Cellular immunodeficiency

(1) The thymus is not easy to be found at autopsy, but scattered thymus reticular tissue can be found under the microscope. The lymphocytes are rare, there is no Hastelloy, and the boundary between cortex and medulla is unclear.

(2) The number of total T cells and CD4+ T cells in peripheral blood decreased, the ratio of CD4/CD8 T cells decreased, TCR was / chain, and T cell dysfunction included: delayed skin allergic reaction, proliferative response and rejection Weakened.

4. Other inspections

Serum alpha-fetoprotein (AFP) carcinoembryonic antigen (CEA) is elevated, liver function is abnormal, urinary 17-ketosteroid (17-Ks) is decreased, and follicle-stimulating hormone (FSH) is increased, and autoantibodies may be present.

5. Pathological examination

Liver biopsy can be found in the infiltration of parenchymal cells and small round cells in the portal vein, characterized by parenchymal nuclear swelling and vacuolar degeneration. Many organs, such as the central nervous system, anterior pituitary, thyroid, adrenal gland, liver, kidney, lung, Abnormal cell morphology of the heart, thymus, smooth muscle and spinal ganglion cells, including giant, deformed and deep chromatin nuclei.

Auxiliary inspection

1. Imaging examination

Chest X-ray plain film common thymus deficiency and lung infection; skull CT examination showed ventricular dilatation and diffuse brain atrophy.

2. Other

EEG, EMG examination can be abnormal.


Diagnosis and diagnosis of pediatric ataxia telangiectasia syndrome

According to the clinical manifestations and immunological examination can be confirmed, the foreign application of ATM3BA antibody immuno-hybrid method to directly detect the mutation of the ATM gene for diagnosis, some children begin to appear ataxia, without telangiectasia and immunodeficiency, need long-term Follow-up, sometimes only a few years after the typical performance.

The so-called "partial ATS" clinical phenotype, manifested as a combination of ataxia, immunodeficiency, and chromosomal instability, but no telangiectasia, suggesting that these diseases may be closely related to ATS, or a variant of ATS, The clinical manifestations of Nijmegen's rupture syndrome resemble ATS, with microcephaly, sometimes with mental retardation, but no ataxia and telangiectasia.

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