Aim: Ataxia telangiectasia is a rare autosomal recessive neurodegenerative disorder. In this retrospective study, it was aimed to evaluate immunological abnormalities and secondary diseases during the course of the patients with AT.
Material and Method: Twenty patients diagnosed as ataxia telangiectasia were retrospectively evaluated in this study. The initial complaints, age at diagnosis, consanguinity of the parents, similar disease history or death of the siblings, the distribution of lymphocyte subset, level of immunoglobulin and the results of thorax tomography, pathological examination, thyroid hormone and auto-antibody related to the secondary disease, clinical courses were analyzed.
Results: The most frequent complaint at admission was unstable gait and repeated sinopulmonary infections. The most common findings were low immunoglobulin A levels and low number of T helper lymphocytes. Three of the patients developed bronchiectasis and two of the patients developed Hashimoto’s thyroiditis, whereas two patients who suffered from Hodgkin’s lymphoma died due to infections subsequently. 
Conclusions: Several secondary clinical situations may be associated with ataxia telangiectasia. Clinical suspicion of this entity allows an early diagnosis and treatment of complications. Genetic counseling is crucial in the prevention of this disease which has no definitive treatment primarily in communities with a high prevalence of consanguineous marriages.  (Turk Arch Ped 2012; 47: 38-42)

Introduction

Ataxia telangiectasia (AT) is a rare disease characterized by progressive cerebellar ataxia, telengiectasies in the eyes and skin, recurrent sinopulmonary infections and humoral and cellular immune deficiency of variable degree, sensitivity to ionizing radiation and increase in the frequency of cancer (1,2). Telengiectasies are typically observed on the conjunctivae, auricle and nose. It is estimated that the incidence of the disease is one per 40 000-100 000 live births. Boys and girls are affected equally with this disease which is inherited in an autosomal recessive pattern (3). As a result of a mutation in ATM gene localized on the chromosome 11q22-23 which codes a protein in charge of control of cellular cycle chromosomal breaks occur (4,5). Because of disruption of arrangement of chromosomes in lymphocytes the risk of lymphoreticular system cancers including leukemia and lymphoma is increased.
The disease starts between the ages of 1-4 years with imbalanced gait. Oculo-motor apraxia and disarthria are common, but it is difficult to determine these in young children (1). In most patients, telengiectasies occur years after neurological findings (6). Increase in serum alpha feto-protein (AFP) level and immunologic abnormalities are observed in 95% of the patients (7,8).
The neuropathological finding in ataxia telengiectasia is atrophy in the brain cortex related to degeneration in granular and Purkinje cells. Some investigators suggest that neurological abnormalities are related to the degree of atrophy (9).
In this retrospective study, it was aimed to define the immunological abnormalities and secondary diseases observed during the follow-up in patients with AT.

Material and Method

Complaints at presentation, ages at the time of diagnosis, consanguinity between the mother and the father, history of a similar disease or death in siblings, immunological evaluation, serum AFP levels, problems confronted during the follow-up and prognoses of 20 patients who were followed up in the division of Pediatric Immunology were evaluated retrospectively.

Results

The diagnosis of ataxia telengiectasia was made in the presence of progressive cerebellar ataxia and progressive ocular and cutaneous telengiectasia. AT mutation was not tested in any patient. 20 patients (10 girls and 10 boys) were being followed up because of AT. The mean age at the time of diagnosis was 9 years. It was learned that a similar disease was found in one sibling of 9 patients (45%) and in three siblings of one patient. The complaint at presentation in all patients was gait imbalance and this was present from the time when the patients first started to walk. In 13 patients, a history of recurrent sinopulmonary infection was present. Physical examination revealed ataxia, inadequacy in cerebellar tests, telengiectasias in bulbar conjunctivae in all patients and growth retardation was present in 8 patients (40%). Hodgkin lymphoma was found in two patients during follow-up and both were lost because of infection. Hashimoto thyroiditis was found in two patients who presented with a complaint of swelling in the neck. In three patients, bronchiectasia was observed to have developed as a result of recurrent sinopulmonary infection. Cranial magnetic resonance imaging (MRI) in three patients revealed cerebellar atrophy.
Immunglobulin (Ig) measurements of all patients were done before administration of intravenous immunoglobulin (IVIG). 10 patients had IgA deficiency and 8 patients had IgG2 deficiency. Three patients had IgA deficiency alone, 6 patients had IgG2 deficiency and one patient had hypogammaglobulinemia (IgM, IgG and IgG2 deficiency). In 6 patients, the count of helper T lympocytes was found to be decreased. Serum AFP levels were found to be increased in all patients. Kariotype test revealed chromosome instabilities in three patients. IVIG (400mg/kg) every 3 weeks was administered because of recurrent sinopulmonary infections to 8 patients with immunoglobulin G2 deficiency and to one patient with a lower then normal IgG value (Table 1,2).

Discussion

Neurological symptoms and especially cerebellar ataxia is the first clinical feature to occur in AT and is observed in all patients. Ataxia typically occurs a short time after the children start to walk (at the 12-18th months averagely) (10). The first complaint in all of our patients was gait imbalance and this symptom was present from the day when they first started to walk. Telengiectasias is one of the most characteristic findings of the disease and usually occur at the age of 6-8 years (10). In the literature, the age at the time of diagnosis was reported to be related to the occurence of ocular telengiectasias (2). The mean age in our patient group was 9 years and ocular telengiectasias were present in all of our patients at the time of diagnosis.
Although brain MRI is normal in the initial period of the disease, cerebellar atrophy develops a few years after the symptoms start (approximately at the age of 10) (9). Atrophy was found in the cerebellar hemisphere and vermis in our three patients in whom cranial imaging was performed. After increase in serum AFP is defined, AFP level is used in the differential diagnosis. In all of our patients, AFP level was found to be increased at the time of diagnosis. According to the literature the most common humoral immune deficiencies are IgA and IgG2 deficiency and the most common cellular immune deficiency is decreased number of T lymphocytes (10). Similarly, the most common humoral immune deficiencies in our patients were IgA deficiency (76.9%) and IgG2 deficiency (61.5%). In 46.1% of the patients, T lymphocyte count was decreased.
The diagnosis was made clinically in patients with early onset cerebellar ataxia and ocular and cutaneous telengiectasias which are two specific findings of ataxia telengiectasia. In cases where the diagnosis is suspicious, increase in serum AFP level and demonstration of ATM gene mutation are diagnostic. The presence of recurrent sinopulmonary infections and familial history may provide early diagnosis. Since it is an autosomal recessive disease, it is more prevalent in communities in which consanguineous marriages are common like our country (21% in Turkey) (11). In 75% of our patients, consanguineous marriage was present and a history of a similar disease was present in 25%.
Another main finding of the disease is immune deficiency and increased tendency to infections. Different disorders have been described in humoral and cellular immunity. The most common humoral immune deficiencies include IgA deficiency, IgE deficiency and IgG deficiency with a lower rate. IgG2 deficiency may accompany especially in half of the subjects with IgA deficiency. Immunglobulin M may be mildly high. Immunglobulin changes observed in ataxia telengiectasia are not related to decrease in B cell count, but they arise from disruption of cellular differentiation. Decrease in maturation of B cells to plasma cells which synthetize IgA and IgE or decrease in helper T lymphocte function are blamed. In addition, severe combined immune deficiency may be observed (12-15). Ersoy et al. (12) reported IgA deficiency in 51.3% of the subjects and increase in IgM levels in 26.2% of the subjects in their study in which they evaluated clinical and immunological features of 160 subjects with AT. Mild lymphocytopenia may be present in 1/3 of the patients with ataxia telengiectasia. Cytotoxic T cells are decreased. Decrease in antibiotic responses against viral and bacterial antigens may be observed. In addition, no reaction may be obtained in cutaneous delayed type hypersensitivity tests, decrease in lymphoproliferative response against various antigens and mitogens may be found and antibody irresponsiveness may be observed against specific antigens (12-15). Among our patients, IgA deficiceny was found in 10 patients and IgG2 deficiency was found in 8 patients. Three patients had IgA deficiency alone, 6 patients had IgG2 deficiency and one patient had hypogammaglobulinemia (IgM, IgG and IgG2 deficiency). In 6 patients, decrease in helper T lymphocyte count was found.
As a result of humoral and cellular immune deficiency frequently recurring sinopulmonary infections and ultimately bronchiectasia may develop (12). In 13 of our patients, sinopulmonary infection was found. The reasons for lung involvement which is observed frequently in ataxia telengiectasia patients include recurrent sinopulmonary diseases and bronchiectasia, interstitial lung disease/pulmonary fibrosis, aspiration pneumoniae found as a result of neuromuscular abormalities, swallowing difficulty and weakness in respiratory muscles (16). Brochiectasia was found to have developed in three of our patients. Pediatricians should pay attention to lung involvement in AT patients, but it should be kept in mind that imaging tests involving ionizing radiation should be avoided as much as possible. In addition, AT patients should be immunized with pneumococcal vaccine and influenza vaccine should be administered yearly.
Ataxia telengiectasia is one of the main diseases involving disruption of DNA repair. Among this group of diseases, AT like disorder, Nijmegen-Breakage syndrome, Bloom syndrome and centromeric region instability and face anormalies syndrome (ICF syndrome) should be remembered. In the differentiation of these diseases which are all similar to each other and which have autosomal reccesive inheritance, immunological findings and genetic disorders should be considered in addition to specific clinical features of the disease. The fact that AFP level is not high in any of of these diseases except for ataxia telengiectasia is significant in terms of differential diagnosis. High AFP in all of our patients was the most important finding supporting the diagnosis of AT. Disorder in DNA repair may result in loss of tumor inhibiting genes, genomic losses, cell death and formation of new oncogenes. Cancer develops in 1/3 of these patients. The most commonly observed cancer is leukemia and lympomas (13). In this study, Hodgkin lymphoma was found to have developed in 2 patients (10%).
In patients with primary immune deficiency (PID), autoimmune diseases may be observed paradoxically. It has been reported that disruption of the control mechanism of self reactive B and T lymphocytes may lead to this. Autoimmunity is observed more frequently in three PID syndromes including APECED (autoimmune polyendocrinopathy), ALPS (candidiasis, ectrodermal dysplasia, autoimmune lymphoproliferative syndrome) and IPEX (immundisregulation, polyendocrinopathy, enteropathy, X-linked genetic inheritance). However, problems related to autoimmunity may also be observed in other PID diseases including CVID (common variable immune deficiency), Good syndrome and hyperimmunoglubulin M syndrome. Type 1 diabetes and Hashimoto thyroiditis are the most common diseases among autoimmune diseases (17). We could not find any data related to association of Hashimoto thyroditis and AT. In 2 patients with Hashimoto thyroiditis, IgA deficiency was present in addition to IgE deficiency and CD4/CD8 ratio was <1 in both patients. The most common reasons of death in patients with ataxia telengiectasia include cancer and lung infections (8,9). In our group, 2 patients were found to have died with lymphoma and one patient was found to have died with lung infection.
Early diagnosis in the follow-up of patients with AT which has no definite treatment is important in terms of earlier and more successful management of other accompanying problems. To prevent this disease which has no definite treatment avoidance of consanguineous marriages and genetic consultancy are important.

Conflict of interest: None declared.

Address for Correspondence: Ekrem Ünal MD, Erciyes University Medical Faculty, Division of Pediatric Hematology, Kayseri, Turkey
E-mail: drekremunal@yahoo.com.tr-ekremunal@erciyes.edu.tr Received: 05.16.2011 Accepted: 10.19.2011

References

1. Chun HH, Gatti RA. Ataxia telangiectasia, an evolving phenotype. DNA Repair (Amst) 2004;3: 1187-96.[Özet]
2. Cabana MD, Crawford TO, Winkelstein JA, Christensen JR, Lederman HM. Consequences of delayed diagnosis of ataxia telangiectasia. Pediatrics 1998;102: 98-100. [Özet] 
3.  Lavin MF, Concannon P, Gatti RA. Eighth International Workshop on Ataxia-Telangiectasia (ATW8). Cancer Res 1999;59: 3845-9. [Özet] 
4. Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995;286: 1749-53.[Özet] 
5. Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 2003;3: 155-68. [Özet] 
6. Fark AK, Shalev B, Crawford TO, et al. Ocular manifestations of ataxia telangiectasia. Am J Ophthalmol 2002;134: 891-6. [Özet] 
7. Waldmann TA, McIntire KR. Serum alpha-fetoprotein levels in patients with ataxia telangiectasia. Lancet 1972;2: 1112-5. [Özet] 
8. Peterson RDA, Kelly WD, Good RA. Ataxia telangiectasia. Its association with a defective thymus, immunological deficiency disease and malignancy. Lancet 1964;1: 1189-93. [Özet] 
9. Tavani F, Zimmerman RA, Berry GT, Sullivan K, Gatti R, Bingham P. Ataxia telangiectasia: the pattern of cerebellar atrophy on MRI. Neuroradiology 2003;45: 315-9. [Özet] 
10. Gatti RA, Boder E, Vinters HV, Sparkes RS, Norman A, Lange K. Ataxia telangiectasia: an interdisciplinary approach to pathogenesis. Medicine 1991;70: 99-117. [Özet] 
11. Azarsiz E, Gulez N, Edeer Karaca N, Aksu G, Kutukculer N. Consanguinity rate and delay in diagnosis in Turkish patients with combined immunodeficiencies: a single-center study. J Clin Immunol 2011;31: 106-11. [Özet] 
12. Ersoy F, Berkel AI, Sanal O, Oktay H. Twenty-year follow-up of 160 patients with ataxi-telangiectasia. Turk J Pediatr 1991;33: 205-15. [Özet]
13. Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM. Immunodeficiency and infections in ataxia-telangiectasia. J Pediatr 2004;144: 505-11. [Özet] 
14. Sanal O, Ersoy F, Yel L, et al. Impaired IgG antibody production to pneumococcal polysaccharides in patients with ataxia-telangiectasia. J Clin Immunol 1999;19: 326-34. [Özet] 
15. Yeganeh M, Gambineri E, Abolmaali K, et al. Other well-defined immunodeficiencies. In: Rezaei N, Aghamohammadi A, Notarangelo LD (eds). Primary immunodeficiency diseases 1st ed. Berlin: Springer Pres Verlag, 2008: 251-314.  
16. Neeleman C, Verhagen M. Pulmonary function tests in patients with ataxia-telangiectasia: obstructive or restrictive lung dysfunction? Ped Pulmonol 2010;45: 1043-4. [Özet] 
17. Bussone G, Mouthon l. Autoimmune manifestations in primary immune deficiencies. Autoimmunity Rev 2009;8: 332-6.[Özet]