Ataxia-Telangiectasia Syndrome - Usmle case based discussion

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Ataxia-telangiectasia (AT), also known as Louis-Bar syndrome, is an autosomal recessive, multisystem disorder characterized by progressive neurologic impairment, cerebellar ataxia, variable immunodeficiency with susceptibility to sinopulmonary infections, impaired organ maturation, X-ray hypersensitivity, ocular and cutaneous telangiectasia, and a predisposition to malignancy. The responsible gene (ATM gene) causes defective DNA repair due to exposure to UV, gamma, and X-radiation.

The disease is reported worldwide with an estimated frequency of 1 in 100,000 births. It occurs in all races and equally in both sexes.

Death typically occurs in early or middle adolescence, usually from bronchopulmonary infection, less frequently from malignancy, or from a combination of both.


Look For
Bilateral dilated conjunctival vessels, first noticed in the angles of both eyes, spread horizontally in the mid region of the conjunctivae, toward the corneal limb. They may subtly involve the internal ears, the eyelids, cheeks, and the antecubital and popliteal fossae.

Features of aging skin are frequent signs of AT, including gray hair, atrophic and even sclerodermoid facial skin, sometimes with atrophic areas resembling varicella scars.

Pigmentary changes are frequent, occurring in a mottled pattern of hyperpigmentation and hypopigmentation with cutaneous atrophy and telangiectasia. Other skin changes include café au lait spots, usually single rather than multiple; hyperpigmented macules resembling large freckles; vitiligo; seborrheic dermatitis; keratosis pilaris; warts; and, in female patients, hirsutism of the arms and the legs.

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

Diagnostic

Ocular telangiectasias may be mistaken for conjunctivitis; however, the background is pink with conjunctivitis, while telangiectasias are dilated vessels against a white background.

Oculomotor abnormalities can occur resulting in deficiency of both horizontal and vertical saccades. Later on this can actually lead to complete supranuclear paralysis of gaze.

Older children have an appearance of premature aging.

Tests
The most constant markers are elevated levels of AFP and carcinoembryonic antigen and chromosomal abnormalities, especially inversions and translocations involving chromosomes 7 and 14, though neither of these abnormalities is always found, and their demonstration requires specific techniques available in only a few centers.

Immunologic abnormalities
IgA deficiency is found in approximately 70% of patients with AT.
A deficit in IgG2 and IgG4 subclasses has been demonstrated in several patients, and IgE may also be absent or low.
Defects of cellular immunity include a low lymphocyte count, a poor response to skin tests to common antigens, low T-lymphocyte proliferation in the presence of mitogens, and deficient antibody production to viral or bacterial antigens.
Increased chromosomal breakage after exposure of cell cultures to ionizing radiation is of rapidly increasing diagnostic importance, though not yet a routine procedure. Such tests have been considered for the prenatal diagnosis of A-T but are being supplanted by DNA diagnosis.

Protein-truncation testing of the entire ATM complementary DNA (cDNA) reveals as much as 66% of truncating mutations in the group with mutant alleles.

Radiologic findings of decreased or absent adenoidal tissue in the nasopharynx on lateral skull radiographs are so typical in AT that they are of value in confirming the diagnosis.

Electrooculography is valuable in corroborating the characteristic oculomotor abnormality of AT and differentiating AT from Friedreich ataxia.

Management
Provide genetic counseling to all patients with AT and their family members.

Regular surveillance of heterozygotes for cancer should be part of family management. ATM heterozygosity was reported to be a risk factor for breast and lung cancers. ATM carriers are also suggested to be more vulnerable at X-radiation because, in many cases, breast cancer occurrence was preceded by X-ray exposure.
Therapy
No specific treatment is available. Control of secondary infection has been the mainstay of therapy. Prevention of infections by regular injection of immunoglobulins is considered useful.

Treatment of neurologic manifestations is disappointing. Beta-adrenergic blockers may improve fine motor coordination in some cases.

X-rays should be avoided as much as possible.

Deferoxamine was shown to increase genomic stability of AT cells and may present a promising tool in AT treatment.

• Category

  Ataxia-Telangiectasia