Ataxia-Telangiectasia Clinical Presentation

Updated: Apr 06, 2020
  • Author: Camila K Janniger, MD; Chief Editor: Dirk M Elston, MD  more...
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Presentation

History

Even in classic ataxia-telangiectasia with ataxia and telangiectasia, the onset of clinical symptoms and the rate of progression are variable. Several reports describe differences in the age of presentation and the rates of progression.

Some classify patients in groupings that reflect the clinical heterogeneity. Type I is the classic syndrome with all manifestations described below. Type II lacks some of the typical findings but shows radiosensitivity. Type III has the classic clinical findings but is not radiosensitive. Type IV shows only some clinical features and is not radiosensitive.

Patients with atypical forms of ataxia-telangiectasia are uncommon. Some of these patients lack one or the other of the laboratory markers. These forms raise the question of the genetic heterogeneity of the disease, a question that will be solved by identifying the abnormal gene or genes. All biological markers for ataxia-telangiectasia are absent, and, in several cases, cultured fibroblasts were normally resistant to irradiation. The course is usually more benign and appears to represent a disease distinct from ataxia-telangiectasia.

Repeated sinopulmonary infections are present in 48-81% of patients. One study divided the patients into 3 groups with regard to the occurrence of infections. One third of patients had frequent and severe infections with progressive lung disease. One third of patients had infections but no progressive lung disease. The remaining third had only a normal incidence of infections. A good correlation exists between the occurrence of infections and immunodeficiency as assessed by laboratory tests.

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Physical Examination

The main abnormalities on physical examination are ocular and cutaneous telangiectasia (see images below) and neurologic symptoms (mainly ataxia and abnormal eye movements present in virtually all cases) and choreoathetosis (30-90% of patients).

Face of a boy with ataxia-telangiectasia. Apparent Face of a boy with ataxia-telangiectasia. Apparent ocular telangiectasia.
Close-up view of advanced telangiectasia of the bu Close-up view of advanced telangiectasia of the bulbar conjunctiva.

Ataxia has its onset in infancy, becoming apparent when the child begins to walk (usually from 12-14 mo). From this early stage, ataxia is associated with abnormal head movements and is slowly and steadily progressive; however, the normal development of motor skills between ages 2-5 years tends to mask the progression of ataxia, so that parents may report an actual improvement in gait. At this point, a diagnosis of cerebral palsy, ataxic or athetoid, is frequently made, but children who are affected have a peculiar gait like little clowns; this finding is highly suggestive of ataxia-telangiectasia.

Ataxia is relentlessly progressive, but the pace is variable, even in the same sibship. Beyond age 5 years, the progression of the ataxia becomes increasingly apparent, and misdiagnosis of Friedreich ataxia may be made, particularly if the telangiectasia has not yet appeared. In a study of 70 patients with ataxia-telangiectasia, the incidence of the onset of symptoms of ataxia was 20% prior to age 1 year, 65% before age 2 years, and 85% by age 4 years. At a typical rate of progression, the child requires a wheelchair by age 10 or 11 years, even when muscular strength continues to be good.

Dyssynergia and intention tremor of the extremities become prominent features with age.

Myoclonic jerks of the trunk and the extremities, particularly on intention, occur in some patients with ataxia-telangiectasia but not before age 9 or 10 years.

The myoclonus may result in sudden and frequent falling and, in itself, make the child nonambulatory.

The Romberg sign is negative but is often reported to be positive because of the failure to observe that swaying of the trunk is equally marked with the eyes open or closed.

Slow initiation and performance of all voluntary activity and muscular hypotonia are characteristic and are also manifestations of cerebellar symptomatology.

Deep reflexes may be normal in the younger child, but they are usually diminished or absent after age 7 or 8 years; the plantar responses are flexor or equivocal.

All modalities of sensation are intact, although vibratory and position senses are usually impaired in older patients.

Intact sensation and a negative Romberg sign are helpful in differentiating the cerebellar ataxia of ataxia-telangiectasia from Friedreich ataxia, in which the ataxia is predominantly spinal or sensory and the Romberg sign is positive.

The early absence of spinal signs in younger patients with ataxia-telangiectasia is consistent with the histopathologic findings that significant spinal cord involvement occurs much later than the devastating early cerebellar degeneration.

Choreoathetosis is the most prominent extrapyramidal feature in ataxia-telangiectasia.

Choreoathetosis is seen more in older children than in younger children, in whom the purely cerebellar picture predominates and may be so marked in some patients as to overshadow or mask the ataxia.

A dystonic component is also possible. Rarely, it may be the pivotal symptom. [34]

Characteristic facies and postural attitudes, observed in all of the children, are part of the cerebellar hypotonia and ataxia.

The facies is usually relaxed, dull, sad, and seemingly inattentive, which is in sharp contrast to the cheerful, alert appearance when the patient is smiling.

The hypotonic cerebellar facies, though often described in the literature as masklike, appears so only in older patients with ataxia-telangiectasia, in whom the facial skin has become atrophic and inelastic.

Stooping, with the shoulders drooped and the head sunk forward and usually tilted to one side, becomes the characteristic posture, and gives an impression of muscular weakness and fatigue that contributes to an appearance of premature aging.

Dystonic posturing of the fingers is characteristic.

Oculomotor signs are diagnostically important because they usually precede the appearance of telangiectasias and are steadily progressive.

Saccades are slowly initiated and hypometric so that fixation of a target is obtained by head deviation rather than eye deviation, often in association with a head thrust or a forced blinking (as in Cogan ocular motor apraxia) but is present in both horizontal gaze and vertical gaze.

Eye deviation, when obtained, is saccadic and often halts midway, and optokinetic nystagmus is absent.

More recently, electrooculographic studies have demonstrated the difficulty in initiating voluntary and involuntary saccades, and the increased reaction time of voluntary and involuntary saccades. The oculomotor signs of ataxia-telangiectasia differ from those of other cerebellar degenerations in that they combine features of both cerebellar disorders and extrapyramidal disorders. A later electrooculographic study indicated that the oculomotor abnormality of ataxia-telangiectasia is sufficiently different from that of Friedreich ataxia and was valuable in the differential diagnosis.

Dysarthria of the cerebellar type, characteristic postures, and a dull facies at rest with a slow-spreading smile contribute to the peculiar appearance of children with ataxia-telangiectasia.

About 30% of patients have mild mental retardation. Mental retardation is not a characteristic feature of ataxia-telangiectasia; however, the results of psychometric testing show wide scatter, and intelligence quotient (IQ) scores may drop below the normal range as the disease progresses.

Mental deficiency was reported in one third of patients on whom information was available.

Analysis of serial test results in the early decades of life gives no indication that cognitive function is lost. Rather, the drop in IQ scores that tends to occur as the disease progresses appears to reflect an increasing disparity between the mental age and the chronologic age. It is a leveling off of mental function rather than an actual mental deterioration.

Some older patients in their 20s and 30s have shown a selective severe loss of short-term memory, suggestive of premature aging.

Children with ataxia-telangiectasia are generally socially responsive, appreciative, and undemanding. Parents comment on their children being "easy to take care of" and having "a good sense of humor."

Telangiectasias are a second major clinical manifestation (nonneurologic) of the disease. They have a later onset than ataxia, first noticed after age 3-6 years and sometimes not until adolescence. They may be absent even later in some cases; however, telangiectasia can be observed considerably earlier, particularly if the clinician suspects ataxia-telangiectasia, such as in children with a prior family history.

Dilated conjunctivae vessels, first noticed in the angles of both eyes, spread horizontally in the equatorial region of the conjunctivae toward the corneal limb. They may subtly involve the internal ears, the eyelids, and the cubital and popliteal fossas.

Patches of telangiectasia elsewhere in the skin are less common.

Ocular telangiectasias may be mistaken for conjunctivitis, but they can be readily distinguished because they are dilated vessels against a white background, whereas the background is pink in conjunctivitis. Refer to the image below.

Close-up view of advanced telangiectasia of the bu Close-up view of advanced telangiectasia of the bulbar conjunctiva.

Telangiectatic vessels of ataxia-telangiectasia very rarely hemorrhage.

The telangiectases were originally thought to be arterial in origin, but capillary microscopy indicates that they are predominantly of venous origin and are not arteriovenous fistulas.

Progeric changes of hair and skin are a cardinal feature of ataxia-telangiectasia.

Some gray hairs are usually found, even in young children if carefully looked for; diffuse graying of the hair may continue to increase slightly through adolescence but is no more than normally progressive thereafter.

The facial skin tends to become atrophic and sclerodermoid in adolescence; atrophic areas resembling large varicella scars may appear.

The ears tend to become inelastic.

The wasted face, the scattered gray hairs, the oculocutaneous telangiectasia, and the stooped posture give the older children an appearance of premature aging.

Chronic seborrheic blepharitis is frequent, stimulating in association with the ocular telangiectasia, a blepharoconjunctivitis.

Pigmentary changes were frequent, occurring in a mottled pattern of hyperpigmentation and hypopigmentation with cutaneous atrophy and telangiectasia, similar to the poikiloderma seen in scleroderma, advanced actinodermatitis, or radiodermatitis, and in premature aging. [35]

Other skin changes include the following:

  • Café au lait spots, usually single rather than multiple

  • Frequent hyperpigmented macules resembling large freckles

  • Occasional vitiligo

  • Cutaneous granulomas: These noninfectious findings may precede the diagnosis of this immunodeficiency disorder and two others—combined variable immunodeficiency and severe combined immunodeficiency. [36, 37] These granulomas were evident clinically as red-brownish nodules and infiltrated ulcerative plaques, often evident on the face and limbs. [38] These granulomas have been linked with rubella as a complicating infection. [39]

Seborrheic dermatitis; keratosis pilaris; common warts; and, in female patients, hirsutism of the arms and the legs are also frequently found. Multiple senile keratoses and basal cell carcinomas of the face have been reported in patients in their 20s.

Patients with ataxia-telangiectasia have an elevated incidence of cancers, approximately 100-fold in comparison to the general population. In children, more than 85% of neoplasm cases are acute lymphocytic leukemia or lymphoma. In adults with ataxia-telangiectasia, solid tumors are more frequent. [23]

Lymphoid malignancies in ataxia-telangiectasia are of both B-cell and T-cell origin and include non-Hodgkin lymphoma, Hodgkin lymphoma, and several forms of leukemia. The outcome of Hodgkin disease in patients with ataxia-telangiectasia is worse than in the general population due to advanced disease stage, coexisting chronic lung disease, or frequent application of insufficient doses of chemotherapy. [40] At autopsy, non-Hodgkin lymphoma accounted for approximately 40% of neoplasms detected, leukemias about 20%, and Hodgkin lymphomas about 10%. The increased frequency of lymphoid tumors in ataxia-telangiectasia could possibly be accounted for by a defect in immune surveillance as part of the underlying immunodeficiency; however, the picture is more complex as malignancies are not confined to the lymphoid system.

Hecht and Hecht, in an analysis of 108 patients with ataxia-telangiectasia with 119 neoplasms, reported that 31 (26%) of these were solid tumors varying in the type and the location. [41] Solid tumors include stomach cancer, breast cancer, medulloblastoma, basal-cell carcinoma, ovarian dysgerminoma, hepatoma, uterine leiomyoma, parotid gland cancer, and thyroid cancer. [42, 43] Brain tumors reported in ataxia-telangiectasia patients include medulloblastomas, multiform glioblastomas, and pilocytic astrocytomas. [44] Determination of subsequent risk in patients with ataxia-telangiectasia diagnosed with one type of neoplasm revealed that approximately 25% of patients with solid tumors subsequently developed non-Hodgkin lymphoma or leukemia. A very low risk of subsequent neoplasms existed when the first tumor was lymphoid in origin.

Genetic polymorphism of the ATM gene also plays an important role in the development of lung cancer. As documented by Kim et al, subjects with the A allele at the site (IVS62+60G→A) have a significantly higher risk of lung cancer than those with the G allele. [45]

Retardation of somatic growth with significant dwarfing is observed in a large proportion of the patients. The heights and weights of children aged 4-7 years are typically at the 10th percentile by adolescence. Only an exceptional patient with ataxia-telangiectasia achieves somatic growth at the 50th percentile or beyond. Patients with ataxia-telangiectasia who develop normal puberty are the ones most likely to achieve somatic growth within the normal range.

The stunting of growth is not well understood. Chronic sinopulmonary disease may be a contributing factor, but stunting of growth also occurs in its absence. Other factors may include the hypogonadism typical of ataxia-telangiectasia and the thymic dysplasia. Endocrine studies performed on a number of patients give no evidence of hypothyroidism or hypopituitarism.

Other likely unrelated cutaneous disorders, including acneiform eruptions, may occur in affected children. [46]

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Complications

Early death is frequently due to pulmonary disease, but malignancies are also a common cause. The incidence of malignancy is 60-300 times higher than in healthy persons, and, on autopsy report, 49% of cases had malignant tumors. The most common tumors are lymphoreticular malignancies, especially non-Hodgkin lymphomas, but other kinds of tumors also occur. Malignancies are also more common in obligate heterozygotes than in the general population.

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