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Ataxia-telangiectasia (Louis-Bar syndrome)
Ataxia-Telangiectasia L. R. Brown,
(Louis-Bar
M.D., C. M. Coulam,
A
TAXIA-TELANGIECTASIA is a familial disorder with an autosomalrecessivetransmissionthat ischaracterized chiefly by the appearance, in early childhood, of progressivecerebellarataxia, ocular and cutaneous telangiectases,immunologic deficiencies,absent or deficient thymus gland, and predisposition to infection and malignancy. Madame Louis-Bar’ is credited with one of the first descriptionsof the syndrome in 1941. Boder and SedgwickzV3 and McFarlin and associates9 added further to an ever-growing body of information on this unusualsyndrome with its multisystem involvement. NEUROLOGIC
FEATURES
Typically, the diseasebeginsin early childhood and is often first recognized when the child begins to walk with an unsteady ataxic gait. These cerebellar signs are progressive. Several related neurologic abnormalitieshave been described,such as choreoathetosis, myoclonic jerks, dysarthria, intention tremors, and abnormal extraocular movements.g Neuropathologic studies demonstrate degeneration of Purkinje’s cells and, to a lesser extent, basket and granular cells of the cerebellum. Gross atrophy of the vermis is often present.2’g In a few cases,cerebellar atrophy hasbeen demonstrated by pneumoencepha1ography.r’No other helpful neuroradiologic signshave been described, but new computerized axial tomographic tech-
L. R. Brown, M.D.: Consultant, Department of Diagnostic Roentgenology, Mayo Clinic and Mayo Foundation, and Instructor in Radiology, Mayo Medical School; C. M. Coulam, M.D., Ph.D.: Associate Consultant, Department of Diagnostic Roentgenology, Mayo Clinic and Mayo Foundation; D. F. Reese, M.D.: Consultant, Department of Diagnostic Roentgenology, Mayo Clinic and Mayo Foundation, and Assistant Professor of Radiology, Mayo Medical School, Rochester, Minn. Reprint requests should be addressed to L. R. Brown, M.D., Department of Dingnostic Roentgenology, Mayo Clinic and Mayo Foundation, Rochester, Minn. 55901. 01976 by Grune & Stratton, Inc.
Seminarsin
Roenfgenology,
Vol.
Xl,
No.
1 (January),
1976
Syndrome)
M.D., Ph.D., and D. F. Reese, M.D.
niques may prove helpful in evaluating the cerebellum in this disease. OCULOCUTANEOUS
FEATURES
Telangiectases usually appear later than the ataxia (usually when the child is 2-8 years old).’ Often the first clinical manifestation is a bloodshot appearanceto the eyes due to prominent oculocutaneous vessels,(jfollowed by frank telangiectases of the bulbar conjunctiva (Fig. 1). Later, telangiectasesappear in a butterfly distribution on the face and on exposed portions of the armsand legs. Histologically, the lesionsare dilated venules branching from subcapillary plexuses.13’5Unlike those in Osler-Weber-Rendu syndrome, the telangiectases in ataxia-telangiectasia do not occur within the brain or lung and are not predisposedto hemorrhage. Diffuse premature graying of the scalp hair is also a feature of this disease.Other skin manifestations may occur, including atrophic and sclerodermatous changes, follicular and solar keratoses, basalcell epitheliomas,or eczema.12 UPPER
AND LOWER RESPIRATORY TRACT FEATURES
The patient is predisposedto chronic recurring sinus and pulmonary infections, otitis media, and rhinitis. Evidence indicates that immunologic defects are responsible for the chronic recurring infections. McFarlin and associates9found that patients with ataxia-telangiectasiawho had normal or nearly normal immune responseshad no increaseddifficulty with infections, but that those with abnormal humoral and cellular immune responseshad life-threatening infections throughout the courseof the disease. RobertsI has stated that the primitive bone marrow stem cell differentiates along two pathways: (1) it migrates to the bursal equivalent, where it maturesinto a B lymphocyte and returns to the germinal centers of the lymph nodes and spleen, with the capabilities of being transformed into a plasmacell and producing humoral immuno-
67
68
BROWN,
Fig.
1.
Typical
conjunctival
globulins (antibodies) IgG, IgA, IgM, IgE, and IgD when challenged by an antigen, and (2) it migrates to the thymus, where it matures into a T lymphocyte, which returns to lymph nodes or spleen or other lymphoid tissue and provides the body’s cellular immune protection. In most immunologic diseases only a single pathway will be affected. However, in ataxia-telangiectasia, the predisposition to infection (when it is present) results from a combined depression of multiple parts of the immune system and is not related to any single parameter. ‘*11 Among the more common immunologic abnormalities in ataxia-telangiectasia are absent or reduced IgA and IgE levels in the serum, absent or reduced IgA levels in the saliva, lymphopenia, absence of delayed hypersensitivity, increased survival time of homografts, absent or reduced lymphoid tissue, and absence or structural abnormalities of the thymus gland.4 Many patients suffer from chronic recurring bronchitis and pneumonitis, which often progress to bronchiectasis. They also may have chronic recurring sinusitis. In the lower respiratory infections there is a mixed bacterial flora. ROENTGEN
FINDINGS
Roentgenologically, the sinusesshow evidenceof mucosal thickening or opacification asa result of
COULAM,
AND
REESE
telangiectasia.
chronic recurring sinusitis (Fig. 2E). The lungs show the various manifestations of chronic recurring infections, such asbronchial wall thickening, recurrent pneumonitis,bronchiectasis,fibrosis, and over-aeration (Fig. 2)’ The roentgenogramof the chest often resemblesthat of mucoviscidosis.” As part of the reduction of lymphoid tissuein the body, the adenoidsappear smallon the lateral view of the nasopharynx. This is a helpful sign in differentiating ataxia-telangiectasiafrom mucoviscidosis.The thymus is alsosmallor absent.
COMPLICATING
MALIGNANT
NEOPLASM
The incidence of malignant tumors among patients with primary immunodeficiency is 10,000 times that of the generalage-matchedpopulation. The incidence in ataxia-telangiectasia is higher than in any of the other primary immunodeficiency diseases,approaching 10%.Most of the neoplasms are lymphoreticular or leukemic in nature but approximately 11%are of nonlymphoid types.’ Since very little lymphoid tissue is present in ataxia-telangiectasia, hilar or mediastinal lymphadenopathy seldom accompaniesthe pulmonary infections. Hence, the appearanceof adenopathy is highly suggestiveof lymphoma (Fig. 2 B-D).14
ATAXIA-TELANGIECTASIA
Fig. 2. Young girl with clinical ataxia-telangiectasia since age 1 year. At age 7 years she became worse, and a more rapid downhill course ensued, with death occurring at age 9 years. (A) At age 7. Chronic pneumonia at right lung base, one of many episodes of pulmonary infection. (6) One year later, lymph node enlargement has supervened. (Cl Progressive nodal enlargement. (D) Terminal film. (E) Bilateral opacification of the antra caused by severe chronic sinusitis. Autopsy revealed lymphosarcoma with massive generalized lymphadenopathy, absent thymus, chronic pneumonitis, and diffuse loss of Purkinje’s cells in the cerebellum. (Courtesy of Dr. Phil ippe L’Heureux, Minneapolis, Minn.)
69
70
BROWN,
COULAM,
AND
REESE
REFERENCES 1. Andrews BF, Kopack FM, Bruton OC: A syndrome of ataxia, oculocutaneous telangiectasia, and sinopuhnonary infections. US Armed Forces Med J 11:587-592, 1960 2. Boder E, Sedgwick RP: Ataxia-telangiectasia: A familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection; a preliminary report on seven children, an autopsy and a case history. Univ South CaIif Med Bull 9: 15, 1957 3. Boder E, Sedgwick RP: Ataxia-telangiectasia: A familial syndrome of progressive cerebelhu ataxia, oculocutaneous telangiectasis and frequent pulmonary infection. Pediatrics 21:526-553, 1958 4. Eisen AH, Karpati G, Laszlo T, et al: Immunologic deficiency in ataxia telangiectasia. N Engl J Med 272: 1822,1965 5. Gatti RA, Good RA: Occurrence of malignancy in immunodeficiency diseases: A literature review. Cancer 28:89-98,197l 6. Harris VJ, Seeler RA: Ataxia-telangiectasia and Hodgkin’s disease. Cancer 32: 1415-1420, 1973 7. Jackson HA: A series of cases illustrative of cerebral pathology: Cases of intracranial tumor. Med Times Gaz 2:541-542,1872
8. Louis-Bar D: Sur un syndrome progressif comprenant des telangiectasies capillaires cutanees et conjonctivales symetriques, i disposition naevoi’de et des troubles cerkbelleux. Confm Neurol4:32-42,194l 9. McFarlin DE, Strober W, Waldmann TA: Ataxiatelangiectasia. Medicine 51:281-314, 1972 10. Ozonoff MB: Ataxia-telangiectasia: Chronic pneumonia, sinusitis, and adenoidal hypoplasia. Am J Roentgen01 120:297-299,1974 11. Polmar SH, Waldmann TA, Balestra ST, et al: Immunoglobulin E in immunologic deficiency diseases. I. Relation of IgE and IgA to respiratory tract disease in isolated IgE deficiency, IgA deficiency, and ataxia telangiectasia. J Clin Invest 51:326-330, 1972 12. Reed WB, Epstein WL, Boder E, et al: Cutaneous manifestations of ataxia-telangiectasia. JAMA 195:746753,1966 13. Roberts SR: Immunology and the lung: An overview. Semin Roentgen01 10:7-17, 1975 14. Shackelford GD, McAlister WH: Primary immunodeficiency diseases and malignancy. Am J Roentgen01 123:144-153, 1975 15. Williams HE, Demis DJ, Higdon RS: Ataxia-telangiectasia: a syndrome with characteristic cutaneous manifestations. Arch Dermatol82:937-942,196O
(Louis-Bar
M.D., C. M. Coulam,
A
TAXIA-TELANGIECTASIA is a familial disorder with an autosomalrecessivetransmissionthat ischaracterized chiefly by the appearance, in early childhood, of progressivecerebellarataxia, ocular and cutaneous telangiectases,immunologic deficiencies,absent or deficient thymus gland, and predisposition to infection and malignancy. Madame Louis-Bar’ is credited with one of the first descriptionsof the syndrome in 1941. Boder and SedgwickzV3 and McFarlin and associates9 added further to an ever-growing body of information on this unusualsyndrome with its multisystem involvement. NEUROLOGIC
FEATURES
Typically, the diseasebeginsin early childhood and is often first recognized when the child begins to walk with an unsteady ataxic gait. These cerebellar signs are progressive. Several related neurologic abnormalitieshave been described,such as choreoathetosis, myoclonic jerks, dysarthria, intention tremors, and abnormal extraocular movements.g Neuropathologic studies demonstrate degeneration of Purkinje’s cells and, to a lesser extent, basket and granular cells of the cerebellum. Gross atrophy of the vermis is often present.2’g In a few cases,cerebellar atrophy hasbeen demonstrated by pneumoencepha1ography.r’No other helpful neuroradiologic signshave been described, but new computerized axial tomographic tech-
L. R. Brown, M.D.: Consultant, Department of Diagnostic Roentgenology, Mayo Clinic and Mayo Foundation, and Instructor in Radiology, Mayo Medical School; C. M. Coulam, M.D., Ph.D.: Associate Consultant, Department of Diagnostic Roentgenology, Mayo Clinic and Mayo Foundation; D. F. Reese, M.D.: Consultant, Department of Diagnostic Roentgenology, Mayo Clinic and Mayo Foundation, and Assistant Professor of Radiology, Mayo Medical School, Rochester, Minn. Reprint requests should be addressed to L. R. Brown, M.D., Department of Dingnostic Roentgenology, Mayo Clinic and Mayo Foundation, Rochester, Minn. 55901. 01976 by Grune & Stratton, Inc.
Seminarsin
Roenfgenology,
Vol.
Xl,
No.
1 (January),
1976
Syndrome)
M.D., Ph.D., and D. F. Reese, M.D.
niques may prove helpful in evaluating the cerebellum in this disease. OCULOCUTANEOUS
FEATURES
Telangiectases usually appear later than the ataxia (usually when the child is 2-8 years old).’ Often the first clinical manifestation is a bloodshot appearanceto the eyes due to prominent oculocutaneous vessels,(jfollowed by frank telangiectases of the bulbar conjunctiva (Fig. 1). Later, telangiectasesappear in a butterfly distribution on the face and on exposed portions of the armsand legs. Histologically, the lesionsare dilated venules branching from subcapillary plexuses.13’5Unlike those in Osler-Weber-Rendu syndrome, the telangiectases in ataxia-telangiectasia do not occur within the brain or lung and are not predisposedto hemorrhage. Diffuse premature graying of the scalp hair is also a feature of this disease.Other skin manifestations may occur, including atrophic and sclerodermatous changes, follicular and solar keratoses, basalcell epitheliomas,or eczema.12 UPPER
AND LOWER RESPIRATORY TRACT FEATURES
The patient is predisposedto chronic recurring sinus and pulmonary infections, otitis media, and rhinitis. Evidence indicates that immunologic defects are responsible for the chronic recurring infections. McFarlin and associates9found that patients with ataxia-telangiectasiawho had normal or nearly normal immune responseshad no increaseddifficulty with infections, but that those with abnormal humoral and cellular immune responseshad life-threatening infections throughout the courseof the disease. RobertsI has stated that the primitive bone marrow stem cell differentiates along two pathways: (1) it migrates to the bursal equivalent, where it maturesinto a B lymphocyte and returns to the germinal centers of the lymph nodes and spleen, with the capabilities of being transformed into a plasmacell and producing humoral immuno-
67
68
BROWN,
Fig.
1.
Typical
conjunctival
globulins (antibodies) IgG, IgA, IgM, IgE, and IgD when challenged by an antigen, and (2) it migrates to the thymus, where it matures into a T lymphocyte, which returns to lymph nodes or spleen or other lymphoid tissue and provides the body’s cellular immune protection. In most immunologic diseases only a single pathway will be affected. However, in ataxia-telangiectasia, the predisposition to infection (when it is present) results from a combined depression of multiple parts of the immune system and is not related to any single parameter. ‘*11 Among the more common immunologic abnormalities in ataxia-telangiectasia are absent or reduced IgA and IgE levels in the serum, absent or reduced IgA levels in the saliva, lymphopenia, absence of delayed hypersensitivity, increased survival time of homografts, absent or reduced lymphoid tissue, and absence or structural abnormalities of the thymus gland.4 Many patients suffer from chronic recurring bronchitis and pneumonitis, which often progress to bronchiectasis. They also may have chronic recurring sinusitis. In the lower respiratory infections there is a mixed bacterial flora. ROENTGEN
FINDINGS
Roentgenologically, the sinusesshow evidenceof mucosal thickening or opacification asa result of
COULAM,
AND
REESE
telangiectasia.
chronic recurring sinusitis (Fig. 2E). The lungs show the various manifestations of chronic recurring infections, such asbronchial wall thickening, recurrent pneumonitis,bronchiectasis,fibrosis, and over-aeration (Fig. 2)’ The roentgenogramof the chest often resemblesthat of mucoviscidosis.” As part of the reduction of lymphoid tissuein the body, the adenoidsappear smallon the lateral view of the nasopharynx. This is a helpful sign in differentiating ataxia-telangiectasiafrom mucoviscidosis.The thymus is alsosmallor absent.
COMPLICATING
MALIGNANT
NEOPLASM
The incidence of malignant tumors among patients with primary immunodeficiency is 10,000 times that of the generalage-matchedpopulation. The incidence in ataxia-telangiectasia is higher than in any of the other primary immunodeficiency diseases,approaching 10%.Most of the neoplasms are lymphoreticular or leukemic in nature but approximately 11%are of nonlymphoid types.’ Since very little lymphoid tissue is present in ataxia-telangiectasia, hilar or mediastinal lymphadenopathy seldom accompaniesthe pulmonary infections. Hence, the appearanceof adenopathy is highly suggestiveof lymphoma (Fig. 2 B-D).14
ATAXIA-TELANGIECTASIA
Fig. 2. Young girl with clinical ataxia-telangiectasia since age 1 year. At age 7 years she became worse, and a more rapid downhill course ensued, with death occurring at age 9 years. (A) At age 7. Chronic pneumonia at right lung base, one of many episodes of pulmonary infection. (6) One year later, lymph node enlargement has supervened. (Cl Progressive nodal enlargement. (D) Terminal film. (E) Bilateral opacification of the antra caused by severe chronic sinusitis. Autopsy revealed lymphosarcoma with massive generalized lymphadenopathy, absent thymus, chronic pneumonitis, and diffuse loss of Purkinje’s cells in the cerebellum. (Courtesy of Dr. Phil ippe L’Heureux, Minneapolis, Minn.)
69
70
BROWN,
COULAM,
AND
REESE
REFERENCES 1. Andrews BF, Kopack FM, Bruton OC: A syndrome of ataxia, oculocutaneous telangiectasia, and sinopuhnonary infections. US Armed Forces Med J 11:587-592, 1960 2. Boder E, Sedgwick RP: Ataxia-telangiectasia: A familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection; a preliminary report on seven children, an autopsy and a case history. Univ South CaIif Med Bull 9: 15, 1957 3. Boder E, Sedgwick RP: Ataxia-telangiectasia: A familial syndrome of progressive cerebelhu ataxia, oculocutaneous telangiectasis and frequent pulmonary infection. Pediatrics 21:526-553, 1958 4. Eisen AH, Karpati G, Laszlo T, et al: Immunologic deficiency in ataxia telangiectasia. N Engl J Med 272: 1822,1965 5. Gatti RA, Good RA: Occurrence of malignancy in immunodeficiency diseases: A literature review. Cancer 28:89-98,197l 6. Harris VJ, Seeler RA: Ataxia-telangiectasia and Hodgkin’s disease. Cancer 32: 1415-1420, 1973 7. Jackson HA: A series of cases illustrative of cerebral pathology: Cases of intracranial tumor. Med Times Gaz 2:541-542,1872
8. Louis-Bar D: Sur un syndrome progressif comprenant des telangiectasies capillaires cutanees et conjonctivales symetriques, i disposition naevoi’de et des troubles cerkbelleux. Confm Neurol4:32-42,194l 9. McFarlin DE, Strober W, Waldmann TA: Ataxiatelangiectasia. Medicine 51:281-314, 1972 10. Ozonoff MB: Ataxia-telangiectasia: Chronic pneumonia, sinusitis, and adenoidal hypoplasia. Am J Roentgen01 120:297-299,1974 11. Polmar SH, Waldmann TA, Balestra ST, et al: Immunoglobulin E in immunologic deficiency diseases. I. Relation of IgE and IgA to respiratory tract disease in isolated IgE deficiency, IgA deficiency, and ataxia telangiectasia. J Clin Invest 51:326-330, 1972 12. Reed WB, Epstein WL, Boder E, et al: Cutaneous manifestations of ataxia-telangiectasia. JAMA 195:746753,1966 13. Roberts SR: Immunology and the lung: An overview. Semin Roentgen01 10:7-17, 1975 14. Shackelford GD, McAlister WH: Primary immunodeficiency diseases and malignancy. Am J Roentgen01 123:144-153, 1975 15. Williams HE, Demis DJ, Higdon RS: Ataxia-telangiectasia: a syndrome with characteristic cutaneous manifestations. Arch Dermatol82:937-942,196O