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Immunodeficiency associated with exomphalos-macroglossia-gigantism syndrome
814
May, I973 T h e Journal o/ P E D I A T R I C S
Immunocleficiency associated exomphalos-macroglossia-gigantismsyndrome Severe combined immunodeficiency disease was observed with the exomphalosmacroglossia-gigantism (EMG) syndrome in a female infant who died of Pneumocystis carinii pneumonia and intractable diarrhea. Two mate siblings o/ this patient who died in infancy probably had similar irrtmunodeficieney disease but no overt manifestations of the EMG syndrome. This report considers possible etiologic and pathogenetic relationships between the EMG syndrome and the irramunodefieiency disorder.
Richard J. Greene, Enid F. Gilbert, Shih-Wen Huang, ~ Sheldon Horowitz, Robert L. Levy, Jurgen P. R. Herrmann, and Riehard Hong, Madison, Wis.
T HE exomphalos-macroglossia-gigantism (EMG) syndromet is characterized neonatally by visceromegaly, omphalocele, hypoglycemia, macroglossia, and by postnatal somatic gigantism. These children have a propensity to be born with or to develop malignant neoplasmsY -r Classic severe combined immunodeficiency disease~ is characterized by an extremely small dysplastic thymus, absence of plasma cells, extreme deftFrom the Departments of Pediatrics and Pathology, University of Wisconsin, Center for Health Sciences and Medical School. Suppored by grants [rom the United States Public Health Service (AM-15086), (GM I5422), (AI-00317), and the American Cancer Society (IN-35K 43). Reprint address: Department ot Pediatrics, University of Wisconsir~ Health Sciences Center, Madison, Wis. 53706. *~Allergy Foundation Fellow. t T h e syndrome is also known by the eponyms WiedemannBeckwith or Beckwith-Wiedernann syndrome after the original describers, a, '-' :lZTerminology as Iisted in Fudenberg, H., et al.: Primary immunodeficiencies. Report of a World Health Organization Commiteee, Pediatrics 47: 927, 1971.
Vol. 82, No. 5, pp. 814-820
c'ency of lymphoid cells, peripheral blood lymphopenia, and hypogammaglobulinemia. s,~) In incomplete forms of immunodeficiency the morphologic changes in the lymphoid tissues are less marked, plasma cells may be present, and one or more of the immunoglobulin classes are present in normal or elevated amounts. 1~ This paper reports thymic dysplasia with immunoglobulin abnormalities in a patient with EMG syndrome. Two of her siblings who died in infancy probably had similar immunologic deficiency but no overt manifestations of this syndrome. The relationship between the EMG syndrome and immunodeficiency disease is discussed. CASE R E P O R T S Case 1 (index Case). Patient C. B. was born to a gravida 7, para 6, abortus 1 mother after a full-term, unremarkable pregnancy. Birth weight was 3,850 Gm. At birth, omphalocele and macroglossia were noted. Except for occa-
Volume 82 Number 5
sional vomiting, the baby was well until 6 months of age. From 6 to 10 months she had chronic upper respiratory infections and was hospitalized with multiple episodes of pneumonia. She was treated with injections of gamma globulin and antibiotics. At 10 months the infant developed vomiting, diarrhea, and dehydration. Family history revealed that the first child (Case 2) died at age 9 months of pneumonia. He had had an unusually severe reaction to smallpox vaccination. The second child (Case 3) had a similar reaction to smallpox vaccination and died at age 21 months of necrotizing pneumonia. The third and fourth children are living and well; another child died in an automobile accident. There was no family history of E M G syndrome or any of its usuat manifestations, and there was no history of either autoimmune or immunodeficiency disease. Physical examination at 10 months revealed an emaciated, dehydrated, lethargic female infant who weigher 7.2 Kg. and had a head circumference of 42 cm. She had unusually long eyelashes, wide palpebral fissures, and apparent proptosis. The auricles showed an intertragal bar and focal, well-demarcated, indented areas on the posterior rim of each helix, 1 to 2 ram. in diameter. There was macroglossia and the tongue protruded 1 cm. from the mouth (Fig. 1). The tonsils were not present, and there were no palpable lymph nodes. Rales were audible over the right anterior chest. There was no hepatosplenomegaly or skin eruption. The urinalysis showed 180 to 200 white blood cells per highpower field. Urine obtained from a suprapubic tap grew 75,000 colonies of E. coil per milliliter; the blood culture also grew E. coll. Chest wentgenograms showed right middle and lower lobe pneumonia and diffuse bilateral interstitial pulmonary disease. Initially, she was treated for ten days with ampicillin and kanamycin. Her hospital course was marked by intractable diarrhea and vomiting. She became septic again five days after discontinuation of antibiotic therapy, and she was started on a 10-day course of gentamicin. Because of diarrhea, cachexia, and progressive deterioration of her condition, long-term parenteral nutrition was started. Severe diarrhea persisted in spite of therapy. The patient died on the thirty-seventh hospital day of cardiorespiratory arrest. Case 2. Patient D. B. (brother of Cases 1 and 3) was born on July 21, 1960, after an unremarkable, full-term pregnancy; birth weight was
Immunodeficiency with E M G syndrome
8 15
Fig. 1. Index case (C. B.) showing macroglossia and protruding tongue.
3.2 Kg. During the first 6 months of life he had three upper respiratory tract infections. At 6~2 months he was hospitalized because of a respiratory infection. He was vaccinated for smallpox at 7 months of age. The reaction covered an area of the left arm measuring over 6 cm. in diameter and required a month to resolve. After several episodes of upper respiratory tract infections, he was hospitalized with pneumonia at 8 89 months of age. He died on the third hospital day. No exanthem was noted during his hospital course. The lymphocyte count on admission was less than 500 cells per cubic millimeter. Case 3. Patient S. B. ibrother of Cases 1 and 2) was born on March 24, 1962, after an unremarkable, full-term pregnancy; birth weight was 3.9 Kg. At 2 months of age an abscess of the anus was drained. He was vaccinated at 5 months, and a large area on the left shoulder became involved in a manner similar to that in Case 2. During a respiratory infection at 6 months of age a white blood count of 2,400 cells per cubic millimeter with 264 lymphocytes per cubic millimeter was noted. After recovery, the white blood count was 4,000 cells per cubic
8 16
Greene et aI.
Fig. 2. Lamina propria of ileum of Patient C. B. Neither plasma cells nor lymphocytes are present. (Original magnification •
The Journal o/ Pediatrics May 1973
tively. Multiple white blood cell counts revealed persistent Iymphopenia (less than 2,000 cells per cubic millimeter) and eosinophilia. A liver biopsy was interpreted as indicative of subacute hepatitis. Liver function tests returned to normal by 17 months. From 9 months he had nmltiple episodes of vomiting, diarrhea, and pneumonia with several hospitalizations. At 21 months the patient developed respiratory distress for which he was hospitalized. He died on the first hospital day. A white blood count at that time was 10,400 cells per cubic millimeter with G24 lymphocytes per cubic millimeter. POSTMORTEM
EXAMINATIONS
Case 1.
Fig. 3. Spleen of Patient C. B. Lack of lymphocyte cuff of splenic arteriole. (Original magnification x400.)
Fig. 4. Thymus of Patient C. B. Lack of corticomedullary differentiation and absence of Hassall's corpuscles is apparent. (Original magnification • millimeter with 1,800 Iymphocytes per cubic millimeter and 1,000 eosinophils per cubic millimeter. At 8 months of age he developed hepatitis and was hospitalized. The SGOT and SGPT reached a maximum of 400 to 800 units, respec-
Gross findings. The typical physiognomy of the E M G syndrome was apparent. In addition, there were many other anomaliesF G There was bilateral focal adrenocortical hyperplasia and focal hyperplasia of the upper pole of the spleen. The thymus was hypoplastic and weighed about 2 Gm. The tonsils were absent, and there were only a few small lymph nodes. Microscopic findings. The tongue revealed marked myofibril hypertrophy. Staining of the lungs with methenamine silver stain demonstrated Pneumocystis carinii pneumonia. The lamina propria of the small bowel was devoid of lymphocytes and plasma cells (Fig. 2); there were no Peyer's patches. There was no lymphoid tissue in the appendix. The spleen was composed mainly of reticular cells without lymphoid follicles or periarteriolar lymphoid tissue (Fig. 3). Eosinophilia was present with an extreme paucity of lymphocytes. The lymph nodes were composed mainly of reticular cells; the nodes lacked follicles, lymphocytes, and plasma cells. Eosinophilia was present. The thymus was hypoplastic, lobular without differentiation between medulla and cortex, and lacked Hassall's corpuscles and lymphocytes (Fig. 4). The adrenal glands showed focal hypertrophy of the zona glomerulosa, diffuse cytomegaly in the zona retieularis, and giant ganglion cells in the medulla. There was no evidence of rejection of a skin allograft which had been applied 18 days before death. Fluorescent staining of the spleen
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Immunodeficiency with EMG syndrome
8 17
Table I. Immunologic investigations
Studies CeU-mediated immunity
I
Candida and tuberculin skin tests Skin allograft Lymphocyte studies (Counts per minute -+ S.E.M.) Patient Normal Control 1 Normal Control 2
Results Negative No evidence of rejection after 18 days
Unstimulated
PHA
MLC
262 -+ 56 462 • 104 624 • 108
791 -+ 586 10,373 + 3,444 18,905 +- 6,299
200 +- 8 51,165 -+ 4,316 58,205 -+ 4,358
Antibody-mediated immunity Immunoglobulins (mg./100 ml.) ~
IgG, 330 (normal for age, 279-1,533) IgA, 46 (normal for age, 16-98) IgM, 11 (normal for age, 22-147) Isohemagglutinins Anti B = zero titer (blood type A) Antitetanus antibodies (titer) 1:4, 7 months after 0.5 c.c. tetanus toxoid 1:4, 14 days after 0.5 c.c. tetanus toxoid booster Antipolio antibodies (titer) Type I < 1:16, II < 1:32, I I I < 1:16, 7 months after trivalent oral polio vaccine Type I < 1:16, II < 1:16, III < 1:16, 14 days after trivalent oral polio vaccine booster PHA = phytohemagglutinin,MLC = mixed lymphocyteculture. ~"Normal values from Stiehm, E. 12.., and Fudenberg, H. It.: Pediatrics 37: 715, 1966. with antisera directed against IgG, IgA, and I g M did not reveal immunoglobulin-containing cells. Case 2. Microscopic findings. There was extensive giant cell pneumonia with eosinophilic intranuclear inclusions. Sections of the small intestine showed a paucity of lymphocytes and plasma cells in the lamina propria and no Peyer's patches. T h e spleen was identical to that in Case 1, except for occasional plasma cells and scant periarteriolar lymphoid tissue. T h e thynms and lymph nodes were not available for study. Case 3. Microscopic findings. There was severe necrotizing pneumonia. The gastrointestinal lymphoid tissue and the spleen were identical in appearance to findings in Case 2. T h e lymph nodes were identical to those of Case 1 except for the presence of occasional plasma cells. The thymus was not available for study. IMMUNOLOGIC
INVESTIGATIONS
Immunologic investigation of the index case is detailed in Table 2. Lymphocytes varied between and 0 and 228 total per cubic millimeter except on one occasion
(4725). T h e lymphopenia, the abnormal in vitro lymphocyte studies, and the inability to develop delayed cutaneous hypersensitivity and to reject a skin allograft reflected a severe defect in ceil-mediated immunity. Although serum levels of IgG were only moderately diminished, no significant antibody responses to tetanus or poliovirus could be detected. No isohemagglutinins were present. These findings indicated a defect in humoral immunity as well. DISCUSSION T h e presence of macroglossia, omphalocele, ear anomalies, and adrenocortical cytomegaly established the diagnosis of E M G syndrome in Patient C. B. In addition, she had bilateral focal, demarcated indented areas on the posterior rim of the helix, recently described by Kosseff and associates 17 as a helpful diagnostic sign of the E M G syndrome. However, neither of the male siblings who had died (not examined by us) had any gross features of the syndrome. T h e index case had a variant of classic severe combined immunodeficiency disease in which her immunoglobulin levels were not as markedly depressed as is usually seen. In fact, the serum IgA levels were well within
8 18
Greene et aI.
normal limits, and the IgG was within the lower limits of normal. However, the functional immunoglobulin response was virtually nil. In view of the morphologic and functional deficiency of the thymic-dependent system it seems reasonable to postulate that at least some of the immunoglobulin deficiency may have resulted from " T helper cell "is deficiency. Definitive testing of this point would require a knowledge of thymusdependent and thymus-independent antigens, information not presently available for human systems. In any event, the pathogenetic mechanism for the immunodeficieney in EMG syndrome seems to reside at a point different from that involved in usual severe combined immunodeficiency disease, in which a stem cell defect is postulated. In stem cell disorders, immunoglobulin production ought not to be possible at all. We would, therefore, be inclined to place the major defect in this form of immunodeficiency in the thymus. However, the resultant deficiency state must be differentiated from syndromes such as the one described by DiGeorg@ 9 for here the immunoglobulin production may be nearly normal. It should be noted that the DiGeorge syndrome may represent a special variety of thymic deficiency in which the thymus is essentially normal except for its extremely small size (approximately 10 per cent of normal).e~ In Patient C. B. thymic structure was markedly abnormal. Her two affected brothers probably had a similar immunologic defect. The spleens in Cases 2 and 3 and the lymph nodes in Case 3 were histologically similar to those of the index case; neither child had Peyer's patches and both had significant eosinophilia, a finding which is common in immune deficiency diseases.2~, 22 One child died of a necrotizing pneumonia histologically similar to Pseudomonas pneumonia and the other died of giant cell pneumonia probably due to measles virus. When measles virus is encountered by patients with immunologic deficiency diseases, the resulting infection may be fatal, and they often do not have the typical rash of rubeola 2a (see Case 2). Patients with immune deficiency disease have an enhanced
The ]ournal of Pediatrics May 1973
susceptibility to hepatitis virus '-':~ and have an increased propensity to develop chronic hepatitis. '-'4 This may explain the hepatitis and its prolonged course in Case 3. Extensive information on lymphoid structure and immunity studies in the EMG syndrome is not presently available; however, in two autopsied patients atrophy of the thymus and the splenic follicles was described. ~ The EMG syndrome is associated with an increased incidence of malignancy, a, 4, 6, 7 At least 5 out of nearly 100 reported patients with EMG syndrome have developed malignancy, These include adrenocortical carcinoma,2,~, ~ nephroblastoma,aT, as and gonado. blastoma. 29 We have also seen a patient with a probable brainstem glioma. The occurrence of malignancy in patients with immunodeficiency disease is approximately 10,000 times greater than the expected incidence in a given age group, a~ The increased incidence of neoplasia in these patients may be another manifestation of immune deficiency. Alternatively, malignancy may simply be another expression of the basic genetic defect. It is possible that a causal relationship exists between immunodeficiency and the EMG syndrome for the concurrence of such rare disorders would seem unlikely as a result of chance alone. Some of the anomalies seen in the EMG syndrome may be due to abnormal epithelial-mesodermal interaction during development. If, as a result, thymic epithelial derivative or other inductor elements necessary for normal immunologic maturation are affected, deficient immunity could occur. Variable expression of the condition could result in lack of immunodeficiency (as in most cases), lack of visceral and external manifestations of the EMG syndrome (? Cases 2 and 3), or the combination of severe combined immunodeficiency disease plus the physical features of the EMG syndrome (index case). There is another parallel to the case described here. ~mmunodeficiency is also relatively infrequent in another syndrome, cartilage hair hypoplasia. When found, however, the immunodeficiency state is quite characteristic; it is manifested by neutropenia and unusual
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Immunodeficiency with EMG syndrome 8 1 9
Number 5
susceptibility to varicella and vaecinia virus infections without unusual difficulty with other infectious agents which commonly plague immunodeficiency patients. The clinical features of the immunodeficiency syndrome are so constant that a fortuitous association with cartilage hair hypoplasia seems unlikely.3~, ~o We thank Drs. L. M. Simonson and H. N. Heinz of Sheboygan, Wis., for referral of the patient and for making available the records of the siblings. We thank Dr. F. H. Bach for the in vitro lymphocyte studies.
11.
12.
13.
REFERENCES
1. Beckwith, J. B.: Extreme cytomegaly of the adrenal fetal cortex, omphalocele, hyperplasia of kidneys and pancreas, Leydig-cell hyperplasia: Another syndrome? Transactions of the Annual Meeting of Western Society for Pediatric Research, Los Angeles, Calif. Nov. 11, 1963. 2. Wiedemann, H. R.: Complexe malformatif familial avec hernie ombilicale et macroglossie: Un "syndrome nouveau"? J. Genet. Hum. 13: 223, 1964. 3. Filippi, G., and McKusick, V. A.: The Beckwith-Wiedemann syndrome (the exomphalosmacroglossia-gigantism syndrome): Report of two cases and review of the literature, Medicine 49: 279, 1970. 4. Beckwith, J. B.: Maeroglossia, omphalocele, adrenal cytomegaly, gigantism and hyperplastic visceromegaly, in Bergsma, D., editor: Birth Defects Original Article Series, vol. 5, No. 2, New York, I969, The National Foundation, p. 188. 5. Thorburn, M. J., Wright, E. S., Miller, C. G., and McNeil Smith-Read, E. H.: Exomphalosmacroglossia-gigantism syndrome in Jamaican infants, Am. J. Dis. Child. 119: 316, 1970. 6. Eaton, A. P., and Maurer, W. F.: The Beckwith-Wiedemann syndrome, Am. J. Dis. Child. 122: 520, 1971. 7. Cohen, M. M., Jr., Gorlin, R. J., Feingold, M., and ten BenseI, R. W.: The Beckwith-Wiedemann syndrome, Am. J. Dis. ChiId. 122: 515, 1971. 8. Glanzmann, E., and Riniker, P.: Essentielle Lymphocytophthise: Ein neues Krankheitsbild aus der Sauglingspathologie, Ann. Paediatr. 175: 1, 1950. 9. Hoyer, J. R., Cooper, M. D., Gabrielsen, A. E., and Good, R. A.: Lymphopenic forms of congenital immunologic deficiency diseases, Medicine 47: 201, 1968. 10. Goldman, A. S., Haggard, M. E., McFadden, J., Ritzmann, S. E., Houston, E. W., Bratcher, R. L., Weiss, K. E., Box, E. M., and Szekrenyes, J. W.: Thymie alymphoplasia, lymphoma, and dys-7-globulinemia. Hyper-yA-, normal-yM-, hypo-yG, a-'gD-, and yE globu-
14.
15.
16. 17.
18.
I9.
20. 21.
22.
23. 24. 25.
linernia, plasmacytosis, normal delayed hypersensitivity, severe allergic reactions, and Coomb's positive anemia, Pediatrics 39: 348, 1967. Buckley, R. H., Bradford, W. D., and Butcher, S. R.: Selective immunoglobulin deficiency associated with thymic alymphoplasia, Pediatrics 39: 506, 1967. Fulginiti, V. A., Pearlman, D. S., Reiquam, C. W., Claman, H. N., Hathaway, W. E., Blackburn, W. R., Githens, J. H., and Kempe, C. H.: Dissociation of delayed hypersensitivity and antibody-synthesizing capacities in man, Lancet 2: 5, 1966. Sehaller, J., Ching, Y., Williams, C. P. S., Davis, S. D., Lagunoff, D., and Wedgwood, R. J.: Hypergammaglobulinemia, antibody deficiency, autoimmune haemolytic anemia, and nephritis in an infant with a familial lymphopenic immune defect, Lancet 2: 825, I966. Nahmias, A. J., Griffith, D., Salsbury, C., and Toshida, K.: Thymic aplasia with lymphopenia, plasma cells, and normal immunoglobulins: Relation to measles virus infection, J. A. M. A. 201: 729, 1967. Riker, J. B., Brandt, C. D., Chandra, R., Arrobio, J. O., and Nakano, J. H.: Vaccineassociated poliomyelitis in a child with thymic abnormality, Pediatrics 48: 923, 1971. Herrmann, J. P. R., Gilbert, E. F., and Opitz, J. M.: In preparation. Kosseff, A. L., Herrmann, J., and Opitz, J, M.: The Wiedemann-Beckwith syndrome: Genetic considerations and a diagnostic sign, Lancet 1: 844, 1972. Claman, H. N., and Chaperon, E. A.: Immunological complementation between thymus and marrow cells--a model for the two cell theory of immunoeompetenee, Transplantation Rev. 1: 92, 1969. DiGeorge, A. M.: Congenital absence of the thymus and its immunologic consequences: Concurrence with congenital hypoparathyroidism, in Bergsma, D., editor: Birth Defects Original Article Series, vol. 4, No. 1, New York, 1968, The National Foundation, p. 116. Lischner, H. W., and DiGeorge, A. M.: Role of the thymus in humoral immunity, Lancet 2: 1044, 1969. Miller, M. E., and Hurnmeler, K.: Thymic dysplasia ("Swiss agammaglobulinemia"). II. Morphologic and functional observations, J. PEDIATR. 70: 737, 1967. Jose, D. G., Gatti, R. A., and Good, R. A.: Eosinophilia with Pneumocystis carinii pneumonia and immune deficiency syndromes, J. PEmATR. 79: 748, 1971. Gatti, R. A., and Good, R. A.: The immunological deficiency diseases, Med. Clin. North Am. 54: 281, 1970. Page, A. R., and Good, R. A.: Plasma-celt hepatitis, with special attention to steroid therapy, Am. J. Dis. Child. 99: 288, 1960. Neeman, J., cited by Beekwith, J. B.: Macroglossia, omphalocele, adrenal cytomegaly, gi-
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gantism and hyperplastic visceromegaly, in Bergsma, D., editor: Birth Defects Original Article Series, vol. 5, No. 2, New York, 1969, The National Foundation, p~ 188. 26. Sherman, F. E., Bass, L. W., and Fetterman, G. H.: Congenital metastasizing adrenal cortical carcinoma associated with cytomegaly of the fetal adrenal cortex, Am. J. Clin. Patbol. 30" 439, 1958. 27. Wilson, F. C., Jr., and Orlin, H.: Crossed congenital hemihypertrophy associated with Wilms' tumor, J. Bone Joint Surg. 47: 1609, 1965. 28. Tower, J., and Beck, P. C., cited by Beckwith, J. B.: Maeroglossia, omphalocele, adrenal cytomegaly, gigantism and hypoplastic visceromegaly, in Bergsma, D., editor: Birth Defects Original Article Series, vol. 5, No. 2, New York, 1969, The National Foundation, p. 188.
The Journal of Pediatrics May 1973
29. Beckwith, J. B., cited by Cohen, M. M., Gorlin, R. J., Feingold, M., and ten Bensel, R. W.: The Beekwith-Wiedemann syndrome, Am. J. Dis. Child. 122: 515, 1971. 30. Gatti, R. A., and Good, R. A.: Occurrence of malignancy in immunodeficiency diseases: A literature review, Cancer 28: 89, 1971. 31. Lux, S. E., Johnston, R. B., Jr., August, C. S., Say, B., Penchaszadeh, V. B., Rosen, F. S., and McKusick, V. A.: Chronic neutropenia and abnormal cellular immunity in cartilagehair hypopIasia, N. Engl. J. Med. 282: 231, 1970. 32. McKusick, V. A., Eldridge, R., Hostetler, J. A., Ruangwit, U., and Egeland, J. A.: Dwarfism in the Amish. II. Cartilage-hair hypoplasia~ Bull. Johns Hopkins Hosp. 116: 285, 1965.
May, I973 T h e Journal o/ P E D I A T R I C S
Immunocleficiency associated exomphalos-macroglossia-gigantismsyndrome Severe combined immunodeficiency disease was observed with the exomphalosmacroglossia-gigantism (EMG) syndrome in a female infant who died of Pneumocystis carinii pneumonia and intractable diarrhea. Two mate siblings o/ this patient who died in infancy probably had similar irrtmunodeficieney disease but no overt manifestations of the EMG syndrome. This report considers possible etiologic and pathogenetic relationships between the EMG syndrome and the irramunodefieiency disorder.
Richard J. Greene, Enid F. Gilbert, Shih-Wen Huang, ~ Sheldon Horowitz, Robert L. Levy, Jurgen P. R. Herrmann, and Riehard Hong, Madison, Wis.
T HE exomphalos-macroglossia-gigantism (EMG) syndromet is characterized neonatally by visceromegaly, omphalocele, hypoglycemia, macroglossia, and by postnatal somatic gigantism. These children have a propensity to be born with or to develop malignant neoplasmsY -r Classic severe combined immunodeficiency disease~ is characterized by an extremely small dysplastic thymus, absence of plasma cells, extreme deftFrom the Departments of Pediatrics and Pathology, University of Wisconsin, Center for Health Sciences and Medical School. Suppored by grants [rom the United States Public Health Service (AM-15086), (GM I5422), (AI-00317), and the American Cancer Society (IN-35K 43). Reprint address: Department ot Pediatrics, University of Wisconsir~ Health Sciences Center, Madison, Wis. 53706. *~Allergy Foundation Fellow. t T h e syndrome is also known by the eponyms WiedemannBeckwith or Beckwith-Wiedernann syndrome after the original describers, a, '-' :lZTerminology as Iisted in Fudenberg, H., et al.: Primary immunodeficiencies. Report of a World Health Organization Commiteee, Pediatrics 47: 927, 1971.
Vol. 82, No. 5, pp. 814-820
c'ency of lymphoid cells, peripheral blood lymphopenia, and hypogammaglobulinemia. s,~) In incomplete forms of immunodeficiency the morphologic changes in the lymphoid tissues are less marked, plasma cells may be present, and one or more of the immunoglobulin classes are present in normal or elevated amounts. 1~ This paper reports thymic dysplasia with immunoglobulin abnormalities in a patient with EMG syndrome. Two of her siblings who died in infancy probably had similar immunologic deficiency but no overt manifestations of this syndrome. The relationship between the EMG syndrome and immunodeficiency disease is discussed. CASE R E P O R T S Case 1 (index Case). Patient C. B. was born to a gravida 7, para 6, abortus 1 mother after a full-term, unremarkable pregnancy. Birth weight was 3,850 Gm. At birth, omphalocele and macroglossia were noted. Except for occa-
Volume 82 Number 5
sional vomiting, the baby was well until 6 months of age. From 6 to 10 months she had chronic upper respiratory infections and was hospitalized with multiple episodes of pneumonia. She was treated with injections of gamma globulin and antibiotics. At 10 months the infant developed vomiting, diarrhea, and dehydration. Family history revealed that the first child (Case 2) died at age 9 months of pneumonia. He had had an unusually severe reaction to smallpox vaccination. The second child (Case 3) had a similar reaction to smallpox vaccination and died at age 21 months of necrotizing pneumonia. The third and fourth children are living and well; another child died in an automobile accident. There was no family history of E M G syndrome or any of its usuat manifestations, and there was no history of either autoimmune or immunodeficiency disease. Physical examination at 10 months revealed an emaciated, dehydrated, lethargic female infant who weigher 7.2 Kg. and had a head circumference of 42 cm. She had unusually long eyelashes, wide palpebral fissures, and apparent proptosis. The auricles showed an intertragal bar and focal, well-demarcated, indented areas on the posterior rim of each helix, 1 to 2 ram. in diameter. There was macroglossia and the tongue protruded 1 cm. from the mouth (Fig. 1). The tonsils were not present, and there were no palpable lymph nodes. Rales were audible over the right anterior chest. There was no hepatosplenomegaly or skin eruption. The urinalysis showed 180 to 200 white blood cells per highpower field. Urine obtained from a suprapubic tap grew 75,000 colonies of E. coil per milliliter; the blood culture also grew E. coll. Chest wentgenograms showed right middle and lower lobe pneumonia and diffuse bilateral interstitial pulmonary disease. Initially, she was treated for ten days with ampicillin and kanamycin. Her hospital course was marked by intractable diarrhea and vomiting. She became septic again five days after discontinuation of antibiotic therapy, and she was started on a 10-day course of gentamicin. Because of diarrhea, cachexia, and progressive deterioration of her condition, long-term parenteral nutrition was started. Severe diarrhea persisted in spite of therapy. The patient died on the thirty-seventh hospital day of cardiorespiratory arrest. Case 2. Patient D. B. (brother of Cases 1 and 3) was born on July 21, 1960, after an unremarkable, full-term pregnancy; birth weight was
Immunodeficiency with E M G syndrome
8 15
Fig. 1. Index case (C. B.) showing macroglossia and protruding tongue.
3.2 Kg. During the first 6 months of life he had three upper respiratory tract infections. At 6~2 months he was hospitalized because of a respiratory infection. He was vaccinated for smallpox at 7 months of age. The reaction covered an area of the left arm measuring over 6 cm. in diameter and required a month to resolve. After several episodes of upper respiratory tract infections, he was hospitalized with pneumonia at 8 89 months of age. He died on the third hospital day. No exanthem was noted during his hospital course. The lymphocyte count on admission was less than 500 cells per cubic millimeter. Case 3. Patient S. B. ibrother of Cases 1 and 2) was born on March 24, 1962, after an unremarkable, full-term pregnancy; birth weight was 3.9 Kg. At 2 months of age an abscess of the anus was drained. He was vaccinated at 5 months, and a large area on the left shoulder became involved in a manner similar to that in Case 2. During a respiratory infection at 6 months of age a white blood count of 2,400 cells per cubic millimeter with 264 lymphocytes per cubic millimeter was noted. After recovery, the white blood count was 4,000 cells per cubic
8 16
Greene et aI.
Fig. 2. Lamina propria of ileum of Patient C. B. Neither plasma cells nor lymphocytes are present. (Original magnification •
The Journal o/ Pediatrics May 1973
tively. Multiple white blood cell counts revealed persistent Iymphopenia (less than 2,000 cells per cubic millimeter) and eosinophilia. A liver biopsy was interpreted as indicative of subacute hepatitis. Liver function tests returned to normal by 17 months. From 9 months he had nmltiple episodes of vomiting, diarrhea, and pneumonia with several hospitalizations. At 21 months the patient developed respiratory distress for which he was hospitalized. He died on the first hospital day. A white blood count at that time was 10,400 cells per cubic millimeter with G24 lymphocytes per cubic millimeter. POSTMORTEM
EXAMINATIONS
Case 1.
Fig. 3. Spleen of Patient C. B. Lack of lymphocyte cuff of splenic arteriole. (Original magnification x400.)
Fig. 4. Thymus of Patient C. B. Lack of corticomedullary differentiation and absence of Hassall's corpuscles is apparent. (Original magnification • millimeter with 1,800 Iymphocytes per cubic millimeter and 1,000 eosinophils per cubic millimeter. At 8 months of age he developed hepatitis and was hospitalized. The SGOT and SGPT reached a maximum of 400 to 800 units, respec-
Gross findings. The typical physiognomy of the E M G syndrome was apparent. In addition, there were many other anomaliesF G There was bilateral focal adrenocortical hyperplasia and focal hyperplasia of the upper pole of the spleen. The thymus was hypoplastic and weighed about 2 Gm. The tonsils were absent, and there were only a few small lymph nodes. Microscopic findings. The tongue revealed marked myofibril hypertrophy. Staining of the lungs with methenamine silver stain demonstrated Pneumocystis carinii pneumonia. The lamina propria of the small bowel was devoid of lymphocytes and plasma cells (Fig. 2); there were no Peyer's patches. There was no lymphoid tissue in the appendix. The spleen was composed mainly of reticular cells without lymphoid follicles or periarteriolar lymphoid tissue (Fig. 3). Eosinophilia was present with an extreme paucity of lymphocytes. The lymph nodes were composed mainly of reticular cells; the nodes lacked follicles, lymphocytes, and plasma cells. Eosinophilia was present. The thymus was hypoplastic, lobular without differentiation between medulla and cortex, and lacked Hassall's corpuscles and lymphocytes (Fig. 4). The adrenal glands showed focal hypertrophy of the zona glomerulosa, diffuse cytomegaly in the zona retieularis, and giant ganglion cells in the medulla. There was no evidence of rejection of a skin allograft which had been applied 18 days before death. Fluorescent staining of the spleen
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Immunodeficiency with EMG syndrome
8 17
Table I. Immunologic investigations
Studies CeU-mediated immunity
I
Candida and tuberculin skin tests Skin allograft Lymphocyte studies (Counts per minute -+ S.E.M.) Patient Normal Control 1 Normal Control 2
Results Negative No evidence of rejection after 18 days
Unstimulated
PHA
MLC
262 -+ 56 462 • 104 624 • 108
791 -+ 586 10,373 + 3,444 18,905 +- 6,299
200 +- 8 51,165 -+ 4,316 58,205 -+ 4,358
Antibody-mediated immunity Immunoglobulins (mg./100 ml.) ~
IgG, 330 (normal for age, 279-1,533) IgA, 46 (normal for age, 16-98) IgM, 11 (normal for age, 22-147) Isohemagglutinins Anti B = zero titer (blood type A) Antitetanus antibodies (titer) 1:4, 7 months after 0.5 c.c. tetanus toxoid 1:4, 14 days after 0.5 c.c. tetanus toxoid booster Antipolio antibodies (titer) Type I < 1:16, II < 1:32, I I I < 1:16, 7 months after trivalent oral polio vaccine Type I < 1:16, II < 1:16, III < 1:16, 14 days after trivalent oral polio vaccine booster PHA = phytohemagglutinin,MLC = mixed lymphocyteculture. ~"Normal values from Stiehm, E. 12.., and Fudenberg, H. It.: Pediatrics 37: 715, 1966. with antisera directed against IgG, IgA, and I g M did not reveal immunoglobulin-containing cells. Case 2. Microscopic findings. There was extensive giant cell pneumonia with eosinophilic intranuclear inclusions. Sections of the small intestine showed a paucity of lymphocytes and plasma cells in the lamina propria and no Peyer's patches. T h e spleen was identical to that in Case 1, except for occasional plasma cells and scant periarteriolar lymphoid tissue. T h e thynms and lymph nodes were not available for study. Case 3. Microscopic findings. There was severe necrotizing pneumonia. The gastrointestinal lymphoid tissue and the spleen were identical in appearance to findings in Case 2. T h e lymph nodes were identical to those of Case 1 except for the presence of occasional plasma cells. The thymus was not available for study. IMMUNOLOGIC
INVESTIGATIONS
Immunologic investigation of the index case is detailed in Table 2. Lymphocytes varied between and 0 and 228 total per cubic millimeter except on one occasion
(4725). T h e lymphopenia, the abnormal in vitro lymphocyte studies, and the inability to develop delayed cutaneous hypersensitivity and to reject a skin allograft reflected a severe defect in ceil-mediated immunity. Although serum levels of IgG were only moderately diminished, no significant antibody responses to tetanus or poliovirus could be detected. No isohemagglutinins were present. These findings indicated a defect in humoral immunity as well. DISCUSSION T h e presence of macroglossia, omphalocele, ear anomalies, and adrenocortical cytomegaly established the diagnosis of E M G syndrome in Patient C. B. In addition, she had bilateral focal, demarcated indented areas on the posterior rim of the helix, recently described by Kosseff and associates 17 as a helpful diagnostic sign of the E M G syndrome. However, neither of the male siblings who had died (not examined by us) had any gross features of the syndrome. T h e index case had a variant of classic severe combined immunodeficiency disease in which her immunoglobulin levels were not as markedly depressed as is usually seen. In fact, the serum IgA levels were well within
8 18
Greene et aI.
normal limits, and the IgG was within the lower limits of normal. However, the functional immunoglobulin response was virtually nil. In view of the morphologic and functional deficiency of the thymic-dependent system it seems reasonable to postulate that at least some of the immunoglobulin deficiency may have resulted from " T helper cell "is deficiency. Definitive testing of this point would require a knowledge of thymusdependent and thymus-independent antigens, information not presently available for human systems. In any event, the pathogenetic mechanism for the immunodeficieney in EMG syndrome seems to reside at a point different from that involved in usual severe combined immunodeficiency disease, in which a stem cell defect is postulated. In stem cell disorders, immunoglobulin production ought not to be possible at all. We would, therefore, be inclined to place the major defect in this form of immunodeficiency in the thymus. However, the resultant deficiency state must be differentiated from syndromes such as the one described by DiGeorg@ 9 for here the immunoglobulin production may be nearly normal. It should be noted that the DiGeorge syndrome may represent a special variety of thymic deficiency in which the thymus is essentially normal except for its extremely small size (approximately 10 per cent of normal).e~ In Patient C. B. thymic structure was markedly abnormal. Her two affected brothers probably had a similar immunologic defect. The spleens in Cases 2 and 3 and the lymph nodes in Case 3 were histologically similar to those of the index case; neither child had Peyer's patches and both had significant eosinophilia, a finding which is common in immune deficiency diseases.2~, 22 One child died of a necrotizing pneumonia histologically similar to Pseudomonas pneumonia and the other died of giant cell pneumonia probably due to measles virus. When measles virus is encountered by patients with immunologic deficiency diseases, the resulting infection may be fatal, and they often do not have the typical rash of rubeola 2a (see Case 2). Patients with immune deficiency disease have an enhanced
The ]ournal of Pediatrics May 1973
susceptibility to hepatitis virus '-':~ and have an increased propensity to develop chronic hepatitis. '-'4 This may explain the hepatitis and its prolonged course in Case 3. Extensive information on lymphoid structure and immunity studies in the EMG syndrome is not presently available; however, in two autopsied patients atrophy of the thymus and the splenic follicles was described. ~ The EMG syndrome is associated with an increased incidence of malignancy, a, 4, 6, 7 At least 5 out of nearly 100 reported patients with EMG syndrome have developed malignancy, These include adrenocortical carcinoma,2,~, ~ nephroblastoma,aT, as and gonado. blastoma. 29 We have also seen a patient with a probable brainstem glioma. The occurrence of malignancy in patients with immunodeficiency disease is approximately 10,000 times greater than the expected incidence in a given age group, a~ The increased incidence of neoplasia in these patients may be another manifestation of immune deficiency. Alternatively, malignancy may simply be another expression of the basic genetic defect. It is possible that a causal relationship exists between immunodeficiency and the EMG syndrome for the concurrence of such rare disorders would seem unlikely as a result of chance alone. Some of the anomalies seen in the EMG syndrome may be due to abnormal epithelial-mesodermal interaction during development. If, as a result, thymic epithelial derivative or other inductor elements necessary for normal immunologic maturation are affected, deficient immunity could occur. Variable expression of the condition could result in lack of immunodeficiency (as in most cases), lack of visceral and external manifestations of the EMG syndrome (? Cases 2 and 3), or the combination of severe combined immunodeficiency disease plus the physical features of the EMG syndrome (index case). There is another parallel to the case described here. ~mmunodeficiency is also relatively infrequent in another syndrome, cartilage hair hypoplasia. When found, however, the immunodeficiency state is quite characteristic; it is manifested by neutropenia and unusual
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Immunodeficiency with EMG syndrome 8 1 9
Number 5
susceptibility to varicella and vaecinia virus infections without unusual difficulty with other infectious agents which commonly plague immunodeficiency patients. The clinical features of the immunodeficiency syndrome are so constant that a fortuitous association with cartilage hair hypoplasia seems unlikely.3~, ~o We thank Drs. L. M. Simonson and H. N. Heinz of Sheboygan, Wis., for referral of the patient and for making available the records of the siblings. We thank Dr. F. H. Bach for the in vitro lymphocyte studies.
11.
12.
13.
REFERENCES
1. Beckwith, J. B.: Extreme cytomegaly of the adrenal fetal cortex, omphalocele, hyperplasia of kidneys and pancreas, Leydig-cell hyperplasia: Another syndrome? Transactions of the Annual Meeting of Western Society for Pediatric Research, Los Angeles, Calif. Nov. 11, 1963. 2. Wiedemann, H. R.: Complexe malformatif familial avec hernie ombilicale et macroglossie: Un "syndrome nouveau"? J. Genet. Hum. 13: 223, 1964. 3. Filippi, G., and McKusick, V. A.: The Beckwith-Wiedemann syndrome (the exomphalosmacroglossia-gigantism syndrome): Report of two cases and review of the literature, Medicine 49: 279, 1970. 4. Beckwith, J. B.: Maeroglossia, omphalocele, adrenal cytomegaly, gigantism and hyperplastic visceromegaly, in Bergsma, D., editor: Birth Defects Original Article Series, vol. 5, No. 2, New York, I969, The National Foundation, p. 188. 5. Thorburn, M. J., Wright, E. S., Miller, C. G., and McNeil Smith-Read, E. H.: Exomphalosmacroglossia-gigantism syndrome in Jamaican infants, Am. J. Dis. Child. 119: 316, 1970. 6. Eaton, A. P., and Maurer, W. F.: The Beckwith-Wiedemann syndrome, Am. J. Dis. Child. 122: 520, 1971. 7. Cohen, M. M., Jr., Gorlin, R. J., Feingold, M., and ten BenseI, R. W.: The Beckwith-Wiedemann syndrome, Am. J. Dis. ChiId. 122: 515, 1971. 8. Glanzmann, E., and Riniker, P.: Essentielle Lymphocytophthise: Ein neues Krankheitsbild aus der Sauglingspathologie, Ann. Paediatr. 175: 1, 1950. 9. Hoyer, J. R., Cooper, M. D., Gabrielsen, A. E., and Good, R. A.: Lymphopenic forms of congenital immunologic deficiency diseases, Medicine 47: 201, 1968. 10. Goldman, A. S., Haggard, M. E., McFadden, J., Ritzmann, S. E., Houston, E. W., Bratcher, R. L., Weiss, K. E., Box, E. M., and Szekrenyes, J. W.: Thymie alymphoplasia, lymphoma, and dys-7-globulinemia. Hyper-yA-, normal-yM-, hypo-yG, a-'gD-, and yE globu-
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linernia, plasmacytosis, normal delayed hypersensitivity, severe allergic reactions, and Coomb's positive anemia, Pediatrics 39: 348, 1967. Buckley, R. H., Bradford, W. D., and Butcher, S. R.: Selective immunoglobulin deficiency associated with thymic alymphoplasia, Pediatrics 39: 506, 1967. Fulginiti, V. A., Pearlman, D. S., Reiquam, C. W., Claman, H. N., Hathaway, W. E., Blackburn, W. R., Githens, J. H., and Kempe, C. H.: Dissociation of delayed hypersensitivity and antibody-synthesizing capacities in man, Lancet 2: 5, 1966. Sehaller, J., Ching, Y., Williams, C. P. S., Davis, S. D., Lagunoff, D., and Wedgwood, R. J.: Hypergammaglobulinemia, antibody deficiency, autoimmune haemolytic anemia, and nephritis in an infant with a familial lymphopenic immune defect, Lancet 2: 825, I966. Nahmias, A. J., Griffith, D., Salsbury, C., and Toshida, K.: Thymic aplasia with lymphopenia, plasma cells, and normal immunoglobulins: Relation to measles virus infection, J. A. M. A. 201: 729, 1967. Riker, J. B., Brandt, C. D., Chandra, R., Arrobio, J. O., and Nakano, J. H.: Vaccineassociated poliomyelitis in a child with thymic abnormality, Pediatrics 48: 923, 1971. Herrmann, J. P. R., Gilbert, E. F., and Opitz, J. M.: In preparation. Kosseff, A. L., Herrmann, J., and Opitz, J, M.: The Wiedemann-Beckwith syndrome: Genetic considerations and a diagnostic sign, Lancet 1: 844, 1972. Claman, H. N., and Chaperon, E. A.: Immunological complementation between thymus and marrow cells--a model for the two cell theory of immunoeompetenee, Transplantation Rev. 1: 92, 1969. DiGeorge, A. M.: Congenital absence of the thymus and its immunologic consequences: Concurrence with congenital hypoparathyroidism, in Bergsma, D., editor: Birth Defects Original Article Series, vol. 4, No. 1, New York, 1968, The National Foundation, p. 116. Lischner, H. W., and DiGeorge, A. M.: Role of the thymus in humoral immunity, Lancet 2: 1044, 1969. Miller, M. E., and Hurnmeler, K.: Thymic dysplasia ("Swiss agammaglobulinemia"). II. Morphologic and functional observations, J. PEDIATR. 70: 737, 1967. Jose, D. G., Gatti, R. A., and Good, R. A.: Eosinophilia with Pneumocystis carinii pneumonia and immune deficiency syndromes, J. PEmATR. 79: 748, 1971. Gatti, R. A., and Good, R. A.: The immunological deficiency diseases, Med. Clin. North Am. 54: 281, 1970. Page, A. R., and Good, R. A.: Plasma-celt hepatitis, with special attention to steroid therapy, Am. J. Dis. Child. 99: 288, 1960. Neeman, J., cited by Beekwith, J. B.: Macroglossia, omphalocele, adrenal cytomegaly, gi-
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gantism and hyperplastic visceromegaly, in Bergsma, D., editor: Birth Defects Original Article Series, vol. 5, No. 2, New York, 1969, The National Foundation, p~ 188. 26. Sherman, F. E., Bass, L. W., and Fetterman, G. H.: Congenital metastasizing adrenal cortical carcinoma associated with cytomegaly of the fetal adrenal cortex, Am. J. Clin. Patbol. 30" 439, 1958. 27. Wilson, F. C., Jr., and Orlin, H.: Crossed congenital hemihypertrophy associated with Wilms' tumor, J. Bone Joint Surg. 47: 1609, 1965. 28. Tower, J., and Beck, P. C., cited by Beckwith, J. B.: Maeroglossia, omphalocele, adrenal cytomegaly, gigantism and hypoplastic visceromegaly, in Bergsma, D., editor: Birth Defects Original Article Series, vol. 5, No. 2, New York, 1969, The National Foundation, p. 188.
The Journal of Pediatrics May 1973
29. Beckwith, J. B., cited by Cohen, M. M., Gorlin, R. J., Feingold, M., and ten Bensel, R. W.: The Beekwith-Wiedemann syndrome, Am. J. Dis. Child. 122: 515, 1971. 30. Gatti, R. A., and Good, R. A.: Occurrence of malignancy in immunodeficiency diseases: A literature review, Cancer 28: 89, 1971. 31. Lux, S. E., Johnston, R. B., Jr., August, C. S., Say, B., Penchaszadeh, V. B., Rosen, F. S., and McKusick, V. A.: Chronic neutropenia and abnormal cellular immunity in cartilagehair hypopIasia, N. Engl. J. Med. 282: 231, 1970. 32. McKusick, V. A., Eldridge, R., Hostetler, J. A., Ruangwit, U., and Egeland, J. A.: Dwarfism in the Amish. II. Cartilage-hair hypoplasia~ Bull. Johns Hopkins Hosp. 116: 285, 1965.