Ataxia-Telangiectasia Clinical and Laboratory Features: Single Center Results

Abstract

Ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, chronic sinopulmonary disease, a high incidence of malignancy, and immunological deficiencies. The mutated gene, ataxia-telangiectasia mutation (ATM), has been mapped to chromosome 11 (11q22-23). The incidence of A-T is about 1–3 per 40,000–100,000 births. The aim of this study was to evaluate the clinical and immunological features of the patients with A-T. Medical records of 49 patients with A-T were reviewed retrospectively. Demographic features, laboratory findings, genetic analysis, and the clinical data recorded during the follow-up period were reviewed. Medical records of 49 patients (26 female) were included in the study. Mean age at the time of study was 9 years 3 months. Mean follow-up period was 4.5 years. Mean diagnostic delay was 18 months. Consanguinity was found in 85.7% of the patients. Malignancy was present in 8.2% of first-degree and in 34.7% of second-degree relatives. Lymphocytopenia was found in 29 (59.2%) patients. Mean serum alpha-fetoprotein level was 171.6 ± 138.6 ng/dL. Intravenous immunoglobulin replacement therapy was required in 28 (57.1%) patients. Sinopulmonary infections were the most common infections (51%). Fifteen (30.6%) patients became wheelchair dependent. Malignancy occurred in 6 (12.3%) patients. One patient with acute lymphoblastic leukemia had successful bone narrow transplantation. The other 5 patients died during the follow-up period. Mutation in ATM was found in 34 (69.4%) patients. Of these, 7 patients were found to have novel mutations. A-T is difficult to treat and has a poor prognosis because of its multisystem involvement. Management strategies focus on the surveillance, prevention, and treatment of the major causes of morbidity related to A-T.

Introduction

Ataxia-telangiectasia (A-T) is a rare, autosomal recessive, neurodegenerative disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, chronic sinopulmonary disease, a high incidence of malignancy, and various immunological deficiencies of humoral and cellular immunities.¹ The incidence of A-T is about 1–3 per 40,000–100,000 births.² A-T occurs equally in males and females.³

The mutated gene responsible for A-T is known as A-T gene, which has been mapped to the long arm of chromosome 11 (11q22-23), and the mutation is termed as ataxia-telangiectasia mutation (ATM). The gene product is a DNA-dependent protein kinase localized predominantly in the nucleus and involved in mitogenic signal transduction, meiotic recombination, and cell cycle control. Cells from patients, as well as heterozygous carriers, have an increased sensitivity to ionizing radiation, defective DNA repair, and frequent chromosomal abnormalities.⁴ Ionizing radiation and radiomimetic chemicals lead to chromosome and chromatid breaks. Breakpoints are randomly distributed; however, nonrandom chromosome rearrangements selectively affect chromosomes 7 and 14 at the sites concerned with T cell receptors and heavy chain immunoglobulin coding and with the development of hematological malignancies. Such disturbances could account for frequent infections and neoplasia.⁵

Ataxia is the earliest clinical manifestation of A-T.⁶ Although most children appear healthy during the first year of their lives, they exhibit a loss of gait fluidity. Beyond the age of 5 years, the progression of ataxia becomes apparent and the child requires a wheelchair by 10 or 11 years of age.⁷ Oculocutaneous telangiectasia, the second diagnostic hallmark of A-T, usually has a later onset than ataxia, typically at 3–6 years of age.³

Immune deficiency, which affects both cellular and humoral immunities, occurs in ∼70% of patients with A-T. The defect is quite variable, but often manifests as recurrent sinopulmonary infections.^8,9 The most common abnormalities are low levels of one or more classes of immunoglobulins (IgG, IgA, IgM, or IgG subclasses) and low number of lymphocytes (particularly T lymphocytes) in the blood. Some patients with A-T require antibiotics and/or infusions of immunoglobulins for protection (prophylaxis) against infection.

Patients with A-T have a highly increased incidence (∼25% lifetime risk) of cancers, particularly lymphomas and leukemia.¹⁰ Death typically occurs in early or middle adolescence, usually from bronchopulmonary infection, malignancy (less frequently), or from a combination of both. The median age at death is reported to be ∼20 years.¹¹

The most consistent laboratory abnormality in A-T is an elevation of serum alpha-fetoprotein (AFP) level in children older than 8 months.¹² The level does not necessarily rise over time and does not correlate with the disease severity.

This study aimed to evaluate the clinical and immunological features of patients with A-T.

Materials and Methods

Medical records of patients with A-T were retrospectively reviewed. A-T was diagnosed according to criteria proposed by the European Society for Immunodeficiencies (www.esid.org). Patients with missing medical records were accessed through phone. Patients were excluded if they could not be reached through phone or if their medical records were unavailable. This study was approved by Cukurova University Institutional Review Board and Ethics Committee (Project No: 61/50). Written informed consent was obtained from the parents of each patient who was enrolled.

The following demographic features were recorded: age, gender, family history of intermarriage, relatives with A-T and malignancies, clinical findings, including symptoms, age when the symptoms were first noticed, infections, malignancy, use of a wheelchair, radiation exposure, imaging techniques, survival, and laboratory findings, including a complete blood count, AFP and IgG subclasses levels, and lymphocyte counts. The weight and height of the patients were compared with the mean weight and height for Turkish children of the same gender and age.¹³ Blood samples were analyzed for immunoglobulin levels on the first visit using nephelometric methods, and the results were compared with the normal ranges of quantitative immunoglobulin levels. Lymphocyte subsets were measured by Navios Flow Cytometry (10 colors, 3 lasers) (Beckman Coulter).

To identify the molecular basis, the ATM gene was sequenced using a next-generation sequencing platform (MiSeq System, Illumina). Sequencing was performed in leukocyte DNA for all cases. According to the mutation-positive results, parental screening was also performed for the targeted mutations for carrier status. Therefore, all mutations were confirmed in the parents. In silico analysis was performed using SIFT, Polyphen2 and MutationTaster to define the pathogenicity of novel mutations.

Data analysis was performed using SPSS 15.0 (SPSS, Chicago, IL). The results are expressed as percentages and as mean ± standard deviation (SD) for quantitative variables.

Results

A total of 52 patients with A-T were diagnosed and treated at Cukurova University Medical School Department of Children's Diseases Pediatric Allergy and Immunology Unit between 2000 and 2016. Of these, the medical records of 49 patients (26 females) were retrospectively reviewed; 3 patients were excluded because of missing medical records. Four patients had been diagnosed at another medical center before presenting to our department. The mean age during the study was 9 years 3 months (range, 1.25–19 years). The mean follow-up period was 4.5 years (range, 0.25–13 years). Ataxia was the most common reason for visiting our clinic (Table 1). The majority of patients presented with ataxia (61.2%), 70% of whom had missense mutations, 20% had deletions, 5% had insertions, and 5% had intronic mutations. Delay in walking was the second most common symptom (8.2%) found during diagnosis. In this group, missense mutations were found to be the most common type of mutation (66%). The median age when symptoms were first noticed by parents was 2 years 3 months (range, 0.25–7 years). The mean age at diagnosis was 4 years 6 months (0.9–12.5 years). The mean diagnostic delay was 18 months (range, 0–89 months). Both ataxia and oculocutaneous telangiectasia were diagnosed in all patients. The weight and height of 26 patients (53.1%) were <2 SDs of the mean measurements of the children of the same gender and age. Twenty-three patients (46.9%) had a first- or second-degree relative with A-T. Parental consanguinity was found in 85.7% of the patients. Malignancy was present in 8.2% of the first-degree and in 34.7% of the second-degree relatives (Table 2). These malignancies included lung, stomach, pancreas, colon, liver, thyroid, brain and breast cancers, lymphomas, and leukemia.

Table 1.

Symptoms at Presentation

	n	%
Ataxia	30	61.2
Delay for walking	4	8.2
Family member with A-T	4	8.2
Difficulty of sitting without support	3	6.1
Frequent sinopulmonary infection	3	6.1
Failure to thrive	2	4.1
Difficulty of holding head up high	2	4.1
Frequent falling	2	4.1

A-T, ataxia-telangiectasia.

Table 2.

The Features of Patients with Cancer in Relatives

Patient No.	Gender	Mutation	Consanguinity	Another A-T in family	Malignancy in patient	Malignancy in family
5	Female	p.K1192K (c.3576G>A) homozygous	+	+ (patient 6)	−	Uncle—pancreas cancer
6	Male	p.K1192K (c.3576G>A) homozygous	+	+ (patient 5)	−	Uncle—pancreas cancer
7	Female	No analysis	−	−	ALL	1 Brother—AML, 1 brother—colon cancer
9	Male	c.8395-8404delTTTCAGTGCC homozygous	+	+ (patient 10)	NHL	Aunt—thyroid cancer
10	Female	c.8395-8404delTTTCAGTGCC homozygous	+	+ (patient 9)	−	Aunt—thyroid cancer
15	Male	p.R447^* (c.1339C>T) homozygous	−	−	−	Uncle—ALL; grandfather—lung cancer
20	Female	p.K1192K (c.3536G>A) homozygous	+	+ (patient 21)	−	Brother—AML; cousin—ALL
21	Male	p.K1192K (c.3536G>A) homozygous	+	+ (patient 20)	+	Cousin—ALL
26	Female	IVS42-1G>T (c.6199-1G>T) homozygous	−	Cousin	−	Grandfather—lung cancer
28	Male	p.D1548Tfs^*14 (c.4638_4641delGATA) homozygous	+	−	−	Aunt—gliobastoma
34	Female	p.V835Sfs^*7 (c.2502_2503insA) homozygous	−	−	−	Grandfather—lung cancer
35	Female	No analysis	+	−	−	Grandfather—gastric cancer
36	Female	No analysis	+	−	−	Grandfather—colon cancer
39	Male	No analysis	+	−	−	Uncle—lung cancer
40	Female	No analysis	+	Cousin	−	Uncle—lung cancer
41	Male	No analysis	+	−	−	Uncle—ALL

ALL, acute lymphoblastic leukemia; A-T, ataxia-telangiectasia; AML, acute myeloid leukemia; NHL, non-Hodgkin's lymphoma.

Neutropenia was present in only 1 (2%) patient, whereas lymphocytopenia was found in 29 (59.2%) patients. A T cell subset analysis showed that 30.6% of the patients had CD3+ T cell deficiency. CD4+ T cell lymphocytopenia was detected in 24.5% of the patients. CD19, the determinant of B cell, was deficient in 11 (22.4%) patients. During diagnosis, the most prominent deficient immunoglobulin was IgA, with a rate of 73.5% (range, <6–321). The mean serum IgG level was 856 (range, 109–2,201) mg/dL. Moreover, IgG2 (63.3%) was the most frequently occurring type, followed by IgG4 (49%), IgG3 (46.9%), and IgG1 (10.2%). IgM and IgE were not measured in all patients. The average serum AFP level was 171.6 ± 138.6 (range, 30–506) ng/dL.

During the follow-up period, 28 patients (57.1%) underwent intravenous immunoglobulin (IVIG) replacement therapy. The mean age at the initiation of the IVIG therapy was 5.61 years. Sinopulmonary infections were the most common infections detected in the patients (51%), followed by upper respiratory tract infection (36%), acute gastroenteritis (4.1%), and varicella (2%). Fifteen (30.6%) patients became wheelchair dependent at a mean age of 7.8 years. During the follow-up period, 55.1% of patients were exposed to radiation caused by radiographs (36.2%) or computed tomography (10.2%). Thirteen patients underwent cerebral magnetic resonance and 7 of them were diagnosed with cerebral atrophy (14.3% of all patients). Malignancy was present in 6 (12.3%) patients, including 3 with acute lymphoblastic leukemia (ALL), 1 with acute myeloid leukemia (AML), 1 with non-Hodgkin's lymphoma (NHL), and 1 with Hodgkin's lymphoma (HL). The mean age at diagnosis of malignancy was 10 years 6 months (range, 8–12 years). One patient with ALL underwent a successful bone marrow transplantation. The other 5 patients with malignancy and 1 patient with lung infection and acute respiratory distress syndrome died. The average age at death was 12 years 2 months (range, 9–17 years).

Genetic analysis was performed in 34 (69.4%) patients, all of whom had ATM mutations. According to our results, both exonic and intronic mutations were detected. Most of the mutations in the exonic regions were missense type (n = 22), 7 patients had deletions and 2 of them were insertions. Moreover, there were 3 intronic mutations that were disease causing. All mutations are listed in Table 3. As seen in Table 4, 7 patients (2 of whom were siblings) had 6 different novel homozygous mutations. Each patient's molecular diagnosis was also confirmed by parental studies. Three of the 6 mutations were related to A-T due to a family history of other cases clinically diagnosed as A-T. Interestingly, one of the patients had a history of malignancy in the family; however, we could not contact the family for genetic counseling (Table 4).

Table 3.

The Mutations Found in Our Patients

Patient No.	Missense mutations	Patient No.	Deletions
11	p.E1996^* (c.5986G>T) homozygous/p.G2023R (c.6067G>A) homozygous	37	p.I10fs^*6 (c.27_27delT) homozygous
29	p.D2016Y (c.6046G>T) homozygous	38	p.I10fs^*6 (c.27_27delT) homozygous
41	p.Y2036^* (c.6108T>A) homozygous	9	c.8395-8404delTTTCAGTGCC homozygous
1	p.D2016G (c.6047A>G) homozygous	10	c.8395-8404delTTTCAGTGCC homozygous
2	p.D2016G (c.6047A>G) homozygous	31	p.V128^* (c.381_381delA) homozygous
5	p.K1192K (c.3576G>A) homozygous	27	p.N1554Tfs^*9 (c.4661_4661delA) homozygous
6	p.K1192K (c.3576G>A) homozygous	28	p.D1548Tfs^*14 (c.4638_4641delGATA) homozygous
12	p.K1192K (c.3576G>A) homozygous
15	p.R447^* (c.1339C>T) homozygous	Patient No.	Insertions
16	p.E259E (c.7788G>A) homozygous	17	p.V835Sfs^*7 (c.2502_2503insA) homozygous
18	p.G2063E (c.6188G>A) homozygous	34	p.V835Sfs^*7 (c.2502_2503insA) homozygous
20	p.K1192K (c.3536G>A) homozygous
21	p.K1192K (c.3536G>A) homozygous	Patient No.	Intronic mutations
24	p.D2016G (c.6047A>G) homozygous	19	IVS28+4A>G (c.6137+4A>G) homozygous
25	p.D2016G (c.6047A>G) homozygous	26	IVS42-1G>T (c.6199-1G>T) homozygous
33	p.D2016G (c.6047A>G) homozygous	35	IVS42-1G>T (c.6199-1G>T) homozygous
36	p.D2016G (c.6047A>G) homozygous
39	p.D2016G (c.6047A>G) homozygous
40	p.R447^* (c.1339C>T) homozygous
42	p.K1192K (c.3536G>A) homozygous
43	p.K1192K (c.3536G>A) homozygous
44	p.D2016G (c.6047A>G) homozygous

Table 4.

Novel Mutations Found in Our Patients

Patient No.	Mutation	Consanguinity	Another A-T in family	Malignancy	Malignancy in family
11	p.E1996^* (c.5986G>T) homozygous/p.G2023R (c.6067G>A) homozygous	+	−	−	−
19	IVS28+4A>G (c.6137+4A>G) homozygous	+	−	−	−
29	p.D2016Y (c.6046G>T) homozygous	+	+	−	−
31	p.V128^* (c.381_381delA) homozygous	+	+	−	−
37	p.I10fs^*6 (c.27_27delT) homozygous	−	+	−	−
38	p.I10fs^*6 (c.27_27delT) homozygous	−	+	−	−
41	p.Y2036^* (c.6108T>A) homozygous	+	−	−	+

A-T, ataxia-telangiectasia.

Discussion

A-T, which is also referred as Louis–Bar syndrome,¹⁴ is a rare, neurodegenerative, autosomal recessive disease causing severe disability. Ataxia refers to poor coordination of muscle movements that includes gait abnormality, a hallmark of A-T. The first presenting symptom of A-T is ataxia, which most often appears when children begin to walk. Although patients with A-T usually start walking at a normal age, they wobble or sway when walking, standing still or sitting. Beyond the age of 5 years, progression of ataxia becomes increasingly apparent, and the child requires a wheelchair by the age of 10 or 11 years. Woods and Taylor¹⁵ reported that patients with A-T frequently presented with truncal ataxia at the age of 3 years. In line with the literature, in our study, ataxia was noticed at a mean age of 2.25 (range, 0.25–7) years; it was the earliest symptom in our patients. Moreover, 15 patients required a wheelchair at a mean age of 7.8 years. Telangiectasia is another hallmark of A-T, which typically develops between 3 and 5 years of age. Gatti et al.¹⁶ contended that oculocutaneous telangiectasia eventually occurs in all patients with A-T. Similarly, Maserati et al.¹⁷ reported that A-T patients without telangiectasia are uncommon. In our study, all patients with A-T presented with telangiectasias, with the mean age when symptoms were first noticed being 4.3 years. It is unfortunate that this disease is named A-T because the delayed appearance of telangiectasia often results in delayed diagnosis.¹⁸ Moreover, the mean time between presentation of the first symptom and diagnosis of A-T was 18 (range, 0–89) months. On the contrary, Moin et al.⁵ evaluated 104 patients with A-T and reported the mean time between presentation of the first symptom and diagnosis of A-T to be 58 months.

Patients with A-T have an increased susceptibility to infection. This situation is mostly attributed to immune deficiency, which affects both cellular and humoral immunities and occurs in ∼70% of patients with A-T. The defect in A-T is quite variable, but often manifests as a recurrent sinopulmonary infection.^8,9 Çatal et al.¹⁹ studied 25 patients with A-T in Turkey and reported that 20% of them presented with recurrent otitis media and 72% with recurrent pulmonary infection during follow-up. In our patients, the most common infections were sinopulmonary (51%), followed by upper respiratory tract (36%), acute gastroenteritis (4.1%), and varicella (2%) infections. Immunoglobulin deficiency results from absence or marked reduction of IgA, IgG2, and other IgG subclasses.²⁰ About two-thirds of patients with A-T have low levels or a complete deficiency of IgA, the antibody that protects us from infections on mucosal surfaces. In one study, the IgA deficiency rate was reported to be 75.4%.⁵ In our study, the IgA deficiency rate was 73.5% during diagnosis.

Immunodeficiency in patients with A-T generally remains stable over time, but gets worse with age in ∼15% of the patients. A thorough evaluation by an immunologist is necessary for every patient with A-T to determine whether there is a deficiency of humoral immunity that is severe enough to require immunoglobulin replacement or other therapy. In our study, IVIG replacement therapy was required in 28 (57.1%) patients. The mean age at the initiation of the IVIG therapy was 5.61 years. Most patients with A-T have reduced number of lymphocytes. CD3+ and CD4+ T cell percentages are moderately reduced, with normal or increased percentages of CD8+ T cells.¹ In our study, although neutropenia was present in only 1 (2%) patient, lymphocytopenia was found in 29 (59.2%) patients. A T cell subset analysis showed that 30.6% of patients had CD3+ T cell deficiency. In addition, CD4+ T cell lymphocytopenia was detected in 24.5% of patients. CD19, the determinant of B cell, was deficient in 11 (22.4%) patients.

In appropriate clinical settings, the finding of serum AFP at least 2 SDs above normal for age is diagnostic of the disorder, with a sensitivity of ∼95%. In patients older than 6 months, an AFP level of >30 ng/mL is considered abnormal.²¹ It remains unknown why patients with A-T have elevated AFP levels. AFP level does not necessarily rise over time and does not correlate with the disease severity. In this study, during diagnosis, the mean serum AFP level was 171.6 ± 138.6 (range, 30–506) ng/dL. Similarly, Moin et al.⁵ reported that the mean serum AFP level was 149 ± 137 ng/dL.

A-T is caused by mutations in the ATM gene, which was first cloned in 1995.²² ATM is located on the human chromosome 11 (11q22.3) and comprises 69 exons spread across 150 kb of genomic DNA.²³ Mutation detection in the ATM locus is difficult because of the large size of the gene. Concannon and Gatti discussed the genetic heterogeneity in A-T and provided an update of mutations in the ATM gene.²⁴ In our study, novel ATM mutations were found in 7 patients that were related to the disease both by in silico analysis and parental molecular testing, which showed that the parents were heterozygous for these mutations. Eleven of our patients had nonsense mutations, in which a stop codon replaces an amino acid codon, leading to the termination of translation. Six of these were frameshift mutations, which cause a change in the reading frame that is followed by a stop codon.

A-T is an autosomal recessive disorder. In this pattern of inheritance, each parent is a carrier, meaning that they have 1 normal copy of the A-T gene (ATM) and 1 copy is mutated. A-T occurs if a child inherits the mutated A-T gene from each parent; therefore, in a family with 2 carrier parents, there is 1 chance in 4 that a child born to the parents will have the disorder. Consanguineous marriage may increase the risk of A-T. Swift et al.²⁵ evaluated the results of a prospective study of 1,599 adult blood relatives of patients with A-T with 821 of the spouses distributed in 161 families. In a study conducted in Iran, consanguinity was found in 81.1% of the patients.⁵ In our study, parental consanguinity was found in 85.7% of the patients. In addition, 22 (46.9%) patients had a first- or second-degree relative with A-T.

Patients with A-T have an increased risk for developing all types of cancers, particularly cancers of the immune system (lymphoma or leukemia). The lifetime risk of cancer among patients with A-T has been estimated to be 10%–38%, which is about 100-fold more than the general population rate.²⁶ A-T can occur at any age, and the risk cannot be predicted by the severity of immunodeficiency or by any other feature of the disease. In an autopsy study by Olsen et al.,²⁶ malignant tumors were reported in 49% of the cases. Lymphoreticular malignancies, particularly NHLs, are the most common tumors observed in patients with A-T, but other types of tumors also occur.^27,28 Other tumors reported usually involve the liver, gonads, and stomach.²⁹ In our study, malignancies were present in 6 (12.3%) patients, including 3 with ALL, 1 with AML, 1 with NHL, and 1 with HL. The mean age at diagnosis of malignancy was 10 years 6 months (range, 8–12 years). The estimated risk of all types of cancer among heterozygotes compared with noncarriers is reported to be 3.8 in men and 3.5 in women.²⁵ Morrell et al.³⁰ reported cancer incidence measured retrospectively in 574 close blood relatives of patients with A-T and 213 spouse controls in 44 previously unreported families. In the same study, the relative risk of cancer in heterozygous carriers of the AT gene compared with nonheterozygotes was estimated to be 6.1. Moreover, the most frequent cancer site in the blood relatives was the female breast, with 9 cancers detected in the patients. In this study, malignancies were present in 8.2% of the first-degree and in 34.7% of the second-degree relatives. Only 1 of them had breast cancer, and 4 of them had hematological cancer.

A-T is difficult to treat and has a poor prognosis because of its multisystem involvement. No disease-modifying treatment exists for the ataxic syndrome or the progressive cerebellar neurodegeneration. Many patients with A-T succumb to progressive pulmonary disease caused by repeated infection or to cancer; the median age at death is ∼25 years.³¹ In a retrospective study in the United States, deaths due to all causes of A-T were 50- and 147-fold higher for white and black patients with A-T, respectively, than the expected overall mortality rates in the United States.³² Boder³³ reviewed 58 autopsy cases and reported that 27deaths (46%) were caused by pulmonary infection alone, 12 (21%) by malignancy alone, 16 (28%) by a combination of both, and 3 (5%) by other causes. In a study in Turkey, Çatal et al.¹⁹ studied 25 patients with A-T in which 7 patients died due to several conditions, including NHL (n = 3), pulmonary infection (n = 2), ALL (n = 1), and hemophagocytic lymphohistiocytosis. In our study, 5 patients with malignancies and 1 patient with lung infection and acute respiratory distress syndrome died. The average age at death was 12 years and 2 months (range, 9–17 years).

Conclusion

A-T is difficult to treat and has a poor prognosis because of its multisystem involvement. No specific treatment exists for the ataxic syndrome or the progressive cerebellar neurodegeneration. Many patients succumb to progressive pulmonary disease or to cancer, with the median age at death being ∼25 years. Current management strategies for patients with A-T are based on the treatment of disease manifestations. These strategies focus on the surveillance, prevention, and treatment of the major causes of morbidity related to A-T, including infections, pulmonary disease, immune deficiency, and malignancy.

Moreover, the availability of molecular genetic testing has profound implications for immunologists as well as patients and their families. Genetic testing is beneficial for diagnosis, including presymptomatic screening, prevention, prenatal and preimplantation genetic diagnosis and treatment, as well as prognosis and research.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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