1193

abnormalities suggests that the association is not fortuitous.In the light of recent demonstrations of the relation of thethymus to the development of normal peripheral lym-phoid tissue, immunological capacity, and malignanttumours of lymphoreticular tissue, we are inclined to viewthe observed thymic abnormality in ataxia-telangiectasiaas a probable basis for several of the facets of the

syndrome.In several animal species neonatal thymectomy inhibits

normal maturation of the peripheral lymphoid tissue andsubsequently the immunological system (Good et al. 1962).Development of spontaneous or induced lymphomas inmice depends on an intact thymus (Miller 1961). In thechicken a hind-gut lymphoid organ, the bursa of Fabricius,is required for the development of both full immuno-logical capacity (Glick et al. 1956) and a virus-inducedlymphoma (Peterson, Burmester, et al. 1963).The association of thymic abnormalities and immuno-

logical-deficiency states in man is now well documented(Good and Zak 1956, Tobler and Cottier 1958). Thesimultaneous occurrence in human beings of hypogamma-globulinaemia and lymphoreticular malignancy is alsoknown (Page et al. 1963). The association of a thymicabnormality, immunological deficiency, and lymphoreticu-lar malignancy in several patients with ataxia-telangiectasiasupports a hypothesis relating the human thymus to bothimmunogenesis and leuksemogenesis.The high frequency of lymphocytic malignant tumours

in patients with defective thymic tissue may seem para-doxical in view of the situation observed in animals, wherelymphomas can be prevented by removing the thymus orbursa. This seeming anomaly can be resolved, however, ifthe thymic and bursal tissue is regarded as the principalsite of an abnormal differentiation of lymphoid tissuecaused by genetic abnormalities, viruses, or other oncogenicfactors. An abnormality in the development of theseorgans might ultimately be expressed as a malignantlymphoreticular tumour. Complete removal of the thymusor bursa may remove the site of the abnormal differentia-tion and thereby inhibit the development of the malignantprocess.We postulate that patients with ataxia-telangiectasia

have a genetic defect of one of the components requiredfor the development or maintenance of a normal immuno-logical system. The thymic tissue of our two patients withataxia-telangiectasia resembles that of an embryonicthymus before lymphoid induction. Faulty induction ofthe thymus would be expected to result in a defectiveimmune system. Such a deficiency could be quantitative,and therefore produce a spectrum of immunologicalabnormalities rather than a uniform defect in all patients.Normal mesenchyme is known to be necessary for the

lymphoid maturation of the thymus (Auerbach 1963). Anabnormality in the mesenchyme of patients with ataxia-telangiectasia, perhaps reflected in their vascular lesions,could fail to induce normal lymphoid development of thethymus. An alternative explanation may be that a primaryvascular defect is responsible for the observed thymicabnormality. The progressive degeneration of the centralnervous system in these patients may be secondary to avascular abnormality rather than a primary neuronaldefect. A primary mesenchymal abnormality may thusaccount for all the facets of ataxia-telangiectasia.

SummarySix cases of ataxia-telangiectasia are presented. This

syndrome is commonly associated with a thymic

abnormality, immunological deficiency, and malignancy.The quantitative immunoglobulin determinations were kindly

performed by Dr. Clark West, Dr. Richard Hong, and Dr. Nancy H.Holland. This work was aided by grants from the American CancerSociety, the American Heart Association, the National Foundation,and the U.S. Public Health Service.

REFERENCES

Andrews, B. F., Kopack, F. M., Bruton, O. C. (1960) U.S. Armed Forcesmed. J. 11, 587.

Auerbach, R. (1963) U.S. nat. cancer Inst. Monogr. 11, 23.Biemond, A., von Bolhuis, J. H. (1959) Ned. Tijdschr. Geneesk. 103, 2253.Boder, E., Sedgwick, R. P. (1958) Pediatrics, 21, 526.- - (1963) Little Club Clin. develop. Med. 8, 110.

Brandt, A. (1959) Nord. Med. 62, 1519.Bowden, D. H., Danis, P. (1963) Personal communication.Centerwall, W. R., Miller, M. M. (1958) Amer. J. Dis. Child. 95, 385.Glick, B., Chang, T. S., Jaap, R. G. (1956) Poultry Sci. 35, 224.Good, R. A., Dalmasso, A. P., Martinez, C., Archer, O. K., Pierce, J. C.,

Papermaster, B. W. (1962) J. exp. Med. 116, 773.- Zak, S. J. (1956) Pediatrics, 18, 109.

Gutmann, L., Lemli, L. (1963) Arch. Neurol., Chicago, 8, 318.Hansen, E. (1962) Acta neurol. scand. 38, 188.Hare, W. S., Mackay, I. R. (1963) Lancet, i, 746.Lemli, L. (1963) Personal communication.Louis-Bar, D. (1941) Confin. neurol., Basle, 4, 32.Matthes, A. (1959) Z. Kinderheilk. 82, 292.Miller, J. F. A. P. (1961) Advanc. Cancer Res. 6, 291.Page, A. R., Hansen, A. E., Good, R. A. (1963) Blood, 21, 197.Peterson, R. D. A., Blaw, M., Good, R. A. (1963) J. Pediat. 63, 701.- Burmester, B. H., Fredrickson, T. N., Good, R. A. (1963) J. Lab. clin.Med. 62, 1000.

Pickup, J. D., Pugh, R. J. (1961) Arch. Dis. Childh. 36, 344.Szanto, P. B. (1963) Personal communication.Teller, W. M., Millichap, J. G. (1961) J. Amer. med. Ass. 175, 779.Thieffry, S., Arthuis, M., Aicardi, J., Lyon, G. (1961) Rev. Neurol. Psychiat.

105, 390.Tobler, R., Cottier, H. (1958) Helv. pœdiat. Acta, 13, 313.van der Hoog, C. E. (1959) Maandschr. Kindergeneesk. 27, 26.West, C. D., Hong, R., Holland, N. H. (1962) J. clin. Invest. 41, 2054.

Preliminary Communications

ATAXIA TELANGIECTASIAA DYSGAMMAGLOBULINÆMIA WITH

DEFICIENT &ggr;1A (&bgr;2A)-GLOBULINATAXIA TELANGIECTASIA is a familial syndrome charac-

terised by progressive cerebellar ataxia and oculocutaneoustelangiectasia, and commonly associated with pulmonaryand sinus infections. 1 2 Neurological symptoms appearearly in childhood and patients often succumb to theirpulmonary infections. Several patients have been des-cribed who have had concentrations of y2-globulin as lowas 200 mg. per ml. 3 4; but at best this has not been a con-sistent observation and the yz-globulin levels have beenwell above those ordinarily considered to be in the con-genital agammaglobulinaemic range (0 to 100 mg. per100 ml.).5 Since the reason for the higher susceptibility toinfections in this syndrome has not been well defined, wehave reinvestigated the status of the y-globulins andlymphocytes in children with ataxia telangiectasia.

PATIENTS

Three families have been studied.All of the parents were unrelated, alive, and well, and there

were ten living children (see table). Three children, ages 12years, 7 years, and 15 months appeared to be normal; one child,2 years of age, had mild scleral telangiectasia without neuro-logical symptoms. One child died at 3 months of age with

congenital heart-disease. The other six children had unequi-vocal evidence of ataxia telangiectasia as shown in the table:all six were thought to be normal during the first year of life,and cerebellar ataxia, the initial symptom, was first apparentbetween the ages of 15 months and 4 years. All six had radio-

logical evidence of pansinusitis; three had had several episodesof pneumonia, and one of these (S. S.) developed bronchiectasis,which was demonstrated by bronchography. One patient(E. G.) had only a single clinical episode of pneumonia and two

1. Louis-Bar, D. Confin. Neurol., Basel, 1941, 4, 32.2. Boder, E., Sedgwick, R. P. Pediatrics. 1958, 21, 526.3. Gutmann, L., Lemli, L. Arch. Neurol. 1963, 8, 318.4. Peterson, R. D. A., Blaw, M., Good, R. A. J. Pediat. 1963, 63, 701.5. Gitlin, D., Janeway, C. A. Progr. Hemat. 1956, 1, 318.

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CLINICAL AND IMMUNOCHEMICAL DATA IN SIX CHILDREN WITH ATAXIA TELANGIECTASIA, THEIR SIBLINGS, AND PARENTS

* Concentration of Y1A and Y1M globulin expressed relative to the concentration of a normal human sera pool (N).t One child died at 3 months of congenital heart-disease.1 + to 4+ represents degree of severity of symptoms.

(K. S. and D. G.) had had no evidence of pneumonia. Telangi-ectases were first noted when the patients were between 2 and 5years; it was most readily recognised on the sclerae, but it wasalso present on the ears, the skin over the supraclavicular notch,and the cheeks.

METHODS

The serum immunoglobulins of the patients, their siblings,and their parents were examined by immunoelectrophoresis 6and single and two-dimensional agar-gel precipitation tech-niques, 1 using specific goat, rabbit, and horse anti-human

Fig. 1-Double diffusion in agar. Sera from affected children (D. G.and E. G.), normal sibling (M. G.), parents (Mr. G. and Mrs. G.),and normal serum pool from unrelated children (N) reacted withspecific goat anti-human Y1A-globulin antiserum in centre well.

y-globulin antisera. All antisera used were rendered specific forthe y-globulins by adsorption with serum from a patient withcongenital agammaglobulinsmia. 7S Y2-globulin was estimatedwith Oudin tubes using horse anti-7S y2-globulin antisera, asdescribed elsewhere.5 The serum concentrations of Y1A C&bgr;2A)-globulins and Y1M (p2M)-globulins were quantitated by a two-dimensional agar precipitation method, using goat anti-humanY1A-globulin and goat anti-human Y1M-globulin antisera.

Ability to develop delayed hypersensitivity was determined bytesting with extracts of Candida albicans; all normal childrenover the age of 3 months have delayed hypersensitivity to thisorganism. Inguinal lymph-nodes were obtained by excisionalbiopsy in the six affected children.

RESULTS

The results are shown in the table. Five of the six ataxicpatients had no detectable y,A-globulin and the sixth had a6. Scheidegger, J. J. Int. Arch. Allergy, 1955, 7, 103.7. Oudin, J. Meth. med. Res. 1952. 5.8. Ouchterlony, Ö. Acta Path. Microbiol. scand. 1953, 32, 231.9. Gell, P. G. J. Clin. Path. 1957, 10, 67.

concentration of YIA-globulin which was only one-fourthnormal. All six parents and one unaffected sibling had normalYIA-globulin levels, while one apparently normal child of 12years (M. S.) had a level which was half of normal. The 2-year-old child with mild telangiectasia without ataxia had a YIA-globulin concentration which was half of normal. The child of15 months who had no obvious clinical evidence of this disorderhad a serum-YiA-globulin concentration which was one-fourthof normal; but it must be noted that the earliest evidence of theneurological disturbance did not appear in the affected childrenin this study until 15 months of age. The absence ofyiA-globulinin two affected children and the presence of normal concentra-tions of YlA-globulin in the unaffected sibling and in theirparents are demonstrated in fig. 1. Serum concentrations of7S y2-globulin were normal or slightly elevated in all of the tenliving children and their parents. Serum-yM-globulin con-centrations were definitely increased in one patient (S. S.) andwere either normal or somewhat elevated in the remainingchildren and their parents. Fig. 2 shows an immunoelectro-phoretic analysis of immunoglobulins of one patient (E. G.)demonstrating the absence of the YiA-globulin in the presenceof 7S Y2 and YIM-globulins.

Fig. 2-Immunoelectrophoresis of E. G.’s serum (A and D) andnormal serum pool (B and C) reacted with goat antiserum specificfor human y,A-globulin and rabbit antiserum specific for human7S Ys-gtobulin, y,A-globulin and YIM-globulin.

1195

Total white-blood-cell counts on all patients were in thenormal range; four of the six ataxic children had transient

lymphopenia at some time during the course of their disease,the lymphocyte-count never being below 800 per c.mm. All sixchildren had a normal reaction of delayed hypersensitivity tothe candida extract. None of the six had symptoms suggestiveof immediate hypersensitivity, and direct skin testing for

reagins against ten of the common inhalant allergens, such asragweed, grass, and tree pollens, moulds, and house dust havebeen negative.The general architecture of the lymph-nodes was relatively

normal, but it was distorted by areas of reticulum-cell hyper-plasia. The follicles were less numerous than normal and variedfrom large and hyperplastic to small with degeneration of focalcells. Phagocytosis was absent. There were fewer small lympho-cytes than in normal nodes. Small foci of macrophagescontaining brown pigment were present.

All six patients appeared to be able to swallow normally asindicated by cine-rontgenography.

DISCUSSION

At any rate in the six patients reported here, ataxiatelangiectasia seems to be associated with deficiency ofYA-globulin. Our study does not show whether theYIA-globulin deficiency exists from birth or, like the

neurological and telangiectatic manifestations, developsgradually after 1 or 2 years.In its genetic expression, ataxia telangiectasia appears

to be autosomal recessive. A normal sibling of an affectedpatient may have a partial deficiency of YIA-globulin, butthe parents appear to have normal concentrations. Thedeficiency or absence of YIA-globulins in these patientscould be inherited independently of the neurologicaldisorder and the telangiectasia, but the obvious relationbetween the YIA-globulin deficiency and ataxia telangiec-tasia in our six patients leaves little room for chance, sincethe correlation occurred in three unrelated sibships.

It has been suggested that ataxia telangiectasia is an

expression of thymic dysfunction 4; but our patients withataxia telangiectasia were able to develop delayed hyper-sensitivity and had relatively normal lymph-nodes-conditions which, at least in early life,l° are ordinarilyassociated in man with thymic activity. Transient lymph-openia was noted in several cases, and whether this mightreflect a slight decrease in specific thymic activity or adecrease in the activity of the remainder of the lymphoidsystem could not be ascertained. In one of the patients thelymphopenia was persistent; but even in this child thedegree of lymphopenia was somewhat higher than thatfound in patients with congenital thymic dysfunction orthymic alymphoplasia.10Reagins have been associated, at least in part, with the

Y1A-globulins.u Although, with the allergens tested, skinreactions were negative, the small number of childrenstudied did not allow of definite conclusions about their

ability to synthesise such reagins.It has been thought that cesophageal dysfunction and

aspiration might explain the recurrent pulmonary infec-tions and bronchiectasis endured by these children,2 butall our six patients had normal oesophageal function

radiologically. The possibility exists that aspiration mightoccur during sleep.Whether the ylA-globulin deficiency in these patients is

the cause of their recurrent infections remains to be

10. Gitlin, D., Craig, J. M. Pediatrics, 1963, 32, 517.11. Fireman, P., Vannier, W. E., Goodman, H. C. J. exp. Med. 1963, 117,

603.

decided, but the evidence is suggestive. In any event,ataxia telangiectasia, at least as manifested by the childrenin this report, represents a specific dysgammaglobulin-aemia in which ’Y1A-globulins are deficient or absent where-as 7S Y,A-globulins and y1M-globulins are normal orincreased.

PHILIP FIREMANM.D. Chicago

MARY BOESMANB.S. Juniata Coll.DAVID GITLIN

M.D. New York Univ.

Department of Pediatrics,University of Pittsburgh,

and the Heinz Memorial Laboratories,Children’s Hospital, Pittsburgh,

Pennsylvania, U.S.A.

AN OUTBREAK OF MENINGITIS DUE TOECHO VIRUS TYPE 4 IN SCOTLAND, 1963DISCRETE outbreaks of aseptic meningitis due to

ECHO virus type 4 have occurred in many parts of theworld,l-4 but apart from a few sporadic cases none hasso far been reported in Btitain. During 1963, ECHO-4virus was isolated in this laboratory from forty-onepatients admitted to hospital with aseptic meningitis. Thisagent was also isolated from the small intestine of a femalechild of 2 years in whom multiple intussusceptions andmesenteric adenitis were observed at postmortem. Theoutbreak was first detected in April, and it reached its

peak in August, 1963, the cases arising not only in the

TABLE I-AGE AND SEX DISTRIBUTION OF ECHO-4 CASES

Glasgow area but also in Ayrshire, Lanarkshire, andRenfrewshire. The ages of the patients ranged from8 months to 31 years, with 43% over 10 years (table I).

INVESTIGATIONS

Specimens of faeces and cerebrospinal fluid (C.s.F.) wereexamined for the presence of virus by inoculation into primarytissue-cultures of human amnion and monkey kidney. Virus

isolates were identified by neutralisation tests, using antiserato poliovirus types 1-3, Coxsackie virus types A9 and Bl-6,and ECHO virus types 1-25. Serum specimens from three

I

patients, collected in the acute and convalescent stages ofillness, were examined for ECHO-4 virus-neutralising anti-bodies. The standard methods of this laboratory were used b

throughout these investigations, though daily readings of allEcHO-4 neutralisation tests were essential.

ECHO-4 virus was isolated from the fseces of thirty-fourpatients and from the c.s.F. of nine patients of the forty-twoin this series. Virus was recovered from both the faeces andc.s.F. of one patient. All of these isolations were made in

primary monkey-kidney tissue-cultures. Cytopathic effectswere not visible until 8-13 days after primary inoculation oftissue cultures, and only after three to seven further passageswas reasonably high-titred, virus obtained.

Identification of these isolates presented many technicalproblems. EcHO-4 prototype virus strains are weakly antigenic,thereby making the preparation of hyperimmune serum

difficult. Moreover the antibody response of patients infected1. Karzon, D. T., Eckert, G. L., Barron, A. L., Hayner, N. S., Winkelstein,

Jr., W. Amer. J. Dis. Child. 1961, 101, 610.2. Malherbe, H., Harwin, R. S. Afr. med. J. 1957, 31, 1261.3. Johnsson, T., Böttiger, M., Löfdahl, A. Arch. Virusforsch. 1958, 8, 306.4. Forbes, J. A. Med. J. Aust. 1958, i, 246.5. Bell, E. J., Stott, J., Ross, C. A. C. Arch. Virusforsch. 1964, 14, 147.