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IgA absence associated with short arm deletion of chromosome No. 18
9 64
Brie[ clinical and laboratory observations
other c o m p o u n d s with p o t e n t p h a r m a c o l o g ical effects similar to those f o u n d in our patient? We are grateful to Liam Devlin & Co., Dublin, Ireland, and Geo Bassett & Co., Owterton, Sheffield, England, for much heIp and also for the supply of confections; Messrs. Devlin supplied the crude licorice extract. Dr. C. Nieman of the Centraal Insthuut voor de Dropverwerkende Industrie in Amsterdam kindly carried out glycyrrhizic acid assays and gave much helpful advice. REFERENCES
1. Revers, F. E.: Heef succus liquiritiae een genezende werkig op de magzweer? Nederl. tijdschr, geneesk. 90: 135, 1946. 2. Molhuysen, J. A., Gerbrandy, J., de Vries, L. A., de Jong, J. C., Lenstra, J. B., Turner, K. P., and Borst, J. G. G.: A liquorice extract with deoxycortone-like action, Lancet 2: 381, 1950. 3. Borst, J. G. G., Blomherst, G., Molhuysen, J. A,, Gerbrandy, J:, Turner, K. P., and de Vries, L. A.: De uitscheiding van water en electrolyten gedurende het etmaal in onder invloed van succus liquiritiae, Acta clin. belg. 5: 405, I950
IgA absence associated Mtb short arm deletion of chromosome No. 18 Rogelio H. A. Ruvalcaba, M.D., * and Horace C. Thuline, M.D. SEATTLE
AND BUGKLEY~ WASH.
TH]~ GOEXlSTENGE Of a n E group chromosomal a b n o r m a l i t y with deficiency in a n i m m u n o g l o b u t i n ( I g A ) has been recently r e p o r t e d in 6 instances? -5 T h e I g A was lacking in serum a n d saliva from 3 subjects ~, 4, s a n d in serum w i t h o u t a r e p o r t on
From the Division of Pediatric Endocrinology and Metabolism, Department o[ Pediatrics, University o[ Washington, Seattle, and Rainier School, Buckley. ~Address: Rainier School, BucMey, Wash.
The Journal o[ Pediatrics June 1969
4. Groen, J., Pelser, H., Willebrands, A. F., and Kamminga, C. E.: Extract of licorice for the treatment of Addison's disease, New England J. Med. 244: 471, 1951. 5. Mohamed, S. D., Chapman, R. S., and Crooke, J.: Hypokalaemia, flaccid quadruparesis and myoglobinuria with carbenoxolone (biogastrone), Brit. M. J. 1: 1581, 1966. 6. Doll, R., Hill, I. D., Hutton, G., and Underwood, D. J.: Clinical trial of a triterpenoid liquorice compound in gastric and duodenal ulcer, Lancet 2: 793, 1962. 7. Koster, M., and David, G. K.: Reversible severe hypertension due to licorice ingestion, New England J. Med. 278: !381, 1968. 8. Nieman, C.: Some pharmacological considerations concerning licorice, Brussels, 1958, International Association Confectionery Manufacturers. 9. Revers, F. E.: Enige eigenschappen van succus liquiritiae, Nederl. tijdschr, geneesk. 95: 120, 1951. 10. Cayley, F. E. de W.: Potassium deficiency in paramino-salicylic acid therapy, Lancet 1: 447, 1950. 11. Strong, J. A.: Serum potassium deficiency during treatment with sodium P.A.S. and liquorice extract, Brit. M. J. 2: 998, 1951. 12. Rousak, N. J.: Fatal hypokalaemic alkalosis with tetany during liquorice and P.A.S. therapy, Brit. M. J. 1: 360, 1952.
saliva f r o m 2 of the p a t i e n t s J T h e sixth subject h a d a diminished concentration of I g A only in saliva. 2 T h e karyotypes of p e r i p h e r a l leukocytes a n d skin fibroblast cells of 3 subjects showed a ring No. 18 chromosome. 1-s Apparently IgA i m m u n o g l o b u l l n anomalies in patients with deleted arms of a p a i r No. 18 c h r o m o s o m e have been observed previously only on 3 occasionsa-~; of these, 2 were of the long a n d 1 of the short arm. W e are r e p o r t i n g the case of an 18-year-old Caucasian girl with a m e n t a l age of 9 years who presented the nonspecific p h e n o t y p e characteristics (growth retardation, facial dysmorphia, hypertelorlsm, ptelzygium colli) noted in p r i o r cases w i t h deletion of the short a r m f r o m a chromosome of p a i r No. 18. H e r chromosome a n o m a l y has been confirmed by leukocyte a n d fibroblast culture. Chromosomes of the parents were f o u n d to be normal. I t is of interest t h a t she laad an eczematoid rash on the face d u r i n g infancy, suffered f r o m frequent u p p e r respiratory infections, a n d has had recurrent n o n p a i n f u l
Volume 74 Number 6
Brie] clinical and laboratory observations
Table I. Serum immunoglobulin concentrations
Subject Proposita Mother Father
Immunoglobulin (mg. %)~ Gamma-G [ Gamma-A [ Garnma-M 1,600 2,000
<5 <5
500 300
900
300
420
1,200
370
180
~The immunodiffusion assay technique of Fahey arid McKelveys used gives normal values in milligrams per cent for adults of: IgG, 1,200 + 250 rag.; IgA, 120 "2_ 25 mg.; IgM, 100 + 20 rag.
swelling of the knees. Studies of the synovial fluid obtained by needle puncture of ,he knee showed no inflammatory, cells a n d a bacterial culture was negative. Serum immunoglobulin concentrations for the p r o b a n d and her parents are shown in Table I. I g A was not detected in the serum and' saliva of the patient. T h e I g A concentrations for the parents were normal. T h e mother and patient had a somewhat elevated I g M . Rectal mucosa of the patient was obtained by suction biopsy for immunocytochemical studies; there were plasma cells in the lamina propria, but the normal ratio of I g A to I g M positive plasma cells was reversed. T h e ,patient had blood group A, negative direct and indirect Coombs' test, positive anti-B isohemagglutinins at a titer of 1:128, and a negative Schick test. She received the usual childhood immunization for diphtheria. Routine peripheral blood cell counts, lupus erythematosus preparations, sedimentation rates, serum mucoproteins, antistreptolysin titer, rheumatoid factor, and antinuclear factor were all normal. T h e patient studied by Smith and D a e n t P had a deletion of the short arm of chromosome No. 18~ deficient !gA, and presented with " r h e u m a t o i d arthritis." W e could not establish such a diagnosis for the recurrent swelling of t h e knees observed in our patient. Ever/ though 0.14 to 0.42 per cent of clinically healthy individuals possess no detectabIe !gA, 6 and t h e serum and saliva IgA have been found normal in at least one patient with a ring No. 18 chromosome, ~ the immunoglobulin abnormalities, as well as
96 5
other isolated metabolic defects 7 observed in association with defects of chromosome No. 18, may be more than coincidental. T h e possibility that a gene locus for I g A c a n be shown on one a r m of pair No. 18 has become less simple in view of reports now available. 7 T h e genetic aspects of these cases will be discussed elsewhere. At this time we wish to emphasize the need for immunoglobulin studies of all patients with chromosomal deletions, and for chromosome studies of individuals with multiple congenital anomalies associated with immunologic disorders. The chromosome analyses of the parents were performed at the Joint Cytogenetics Service Laboratory, Rainier School. The serum immunoglobulin and blood analyses were performed at the Immunology Laboratories of the Department of Pediatrics, University of Washington, and in the clinical laboratory of Rainier School. The examination of the rectaI mucosa biopsy was performed by Dr. Shmuel Eidelman, Department of Medicine, University of Washington. The Laboratories of the King County Central Blood Bank, Seattle, performed the isohemagglutin titer. REFERENCES 1. Finley, S. C., Finley, W. H., Noto, T. A., Uchida, I. A., and Roddam R, F.: !gA absence associated with a ring-18 chromosome, Lancet 1: 1095, 1968. 2. Richards, B. W., and I{obbs, J. R.: IgA and ring-18 chromosome, Lancet 1: 1426, 1968. 3. Feingold, M, Schwartz, R . S., Atkins, L., A'nderson, R , Bartsocas, C. S., Page, D. L., arid Littlefield, J. W.: IgA deficiency associated with partial deletion of chromosome 18, J. Clin. Invest. 47: a42, 1968. (Abst.~ 4. Stewart, J., Go, S., Ellis, E., and Robinson, A.: IgA and partial deletions of chromosome18, Lancet 2: 779, 1968. 5. Smith, D., and Daentl, D.: Personal communication. 6. Hanson, L. A.: Aspects 6f the absence of the IgA system in immunologic deficiency diseases in man, in Bergsma, D., and Good, R. A., editors: Birth defects, original article series, vol. IV, No. I, New York, Feb., 1968, The National Foundation-March of Dimes, p. 292. 7. Fraser, G. R.: Partial monosomy 18, Lancet 1: 664, t964, 8. fahey, J.C., and McKelyey, E. M.: Quantitative determination of serum immunoglobulins in antibody agar plates, J. Immunol. 94: 84, 1965.
Brie[ clinical and laboratory observations
other c o m p o u n d s with p o t e n t p h a r m a c o l o g ical effects similar to those f o u n d in our patient? We are grateful to Liam Devlin & Co., Dublin, Ireland, and Geo Bassett & Co., Owterton, Sheffield, England, for much heIp and also for the supply of confections; Messrs. Devlin supplied the crude licorice extract. Dr. C. Nieman of the Centraal Insthuut voor de Dropverwerkende Industrie in Amsterdam kindly carried out glycyrrhizic acid assays and gave much helpful advice. REFERENCES
1. Revers, F. E.: Heef succus liquiritiae een genezende werkig op de magzweer? Nederl. tijdschr, geneesk. 90: 135, 1946. 2. Molhuysen, J. A., Gerbrandy, J., de Vries, L. A., de Jong, J. C., Lenstra, J. B., Turner, K. P., and Borst, J. G. G.: A liquorice extract with deoxycortone-like action, Lancet 2: 381, 1950. 3. Borst, J. G. G., Blomherst, G., Molhuysen, J. A,, Gerbrandy, J:, Turner, K. P., and de Vries, L. A.: De uitscheiding van water en electrolyten gedurende het etmaal in onder invloed van succus liquiritiae, Acta clin. belg. 5: 405, I950
IgA absence associated Mtb short arm deletion of chromosome No. 18 Rogelio H. A. Ruvalcaba, M.D., * and Horace C. Thuline, M.D. SEATTLE
AND BUGKLEY~ WASH.
TH]~ GOEXlSTENGE Of a n E group chromosomal a b n o r m a l i t y with deficiency in a n i m m u n o g l o b u t i n ( I g A ) has been recently r e p o r t e d in 6 instances? -5 T h e I g A was lacking in serum a n d saliva from 3 subjects ~, 4, s a n d in serum w i t h o u t a r e p o r t on
From the Division of Pediatric Endocrinology and Metabolism, Department o[ Pediatrics, University o[ Washington, Seattle, and Rainier School, Buckley. ~Address: Rainier School, BucMey, Wash.
The Journal o[ Pediatrics June 1969
4. Groen, J., Pelser, H., Willebrands, A. F., and Kamminga, C. E.: Extract of licorice for the treatment of Addison's disease, New England J. Med. 244: 471, 1951. 5. Mohamed, S. D., Chapman, R. S., and Crooke, J.: Hypokalaemia, flaccid quadruparesis and myoglobinuria with carbenoxolone (biogastrone), Brit. M. J. 1: 1581, 1966. 6. Doll, R., Hill, I. D., Hutton, G., and Underwood, D. J.: Clinical trial of a triterpenoid liquorice compound in gastric and duodenal ulcer, Lancet 2: 793, 1962. 7. Koster, M., and David, G. K.: Reversible severe hypertension due to licorice ingestion, New England J. Med. 278: !381, 1968. 8. Nieman, C.: Some pharmacological considerations concerning licorice, Brussels, 1958, International Association Confectionery Manufacturers. 9. Revers, F. E.: Enige eigenschappen van succus liquiritiae, Nederl. tijdschr, geneesk. 95: 120, 1951. 10. Cayley, F. E. de W.: Potassium deficiency in paramino-salicylic acid therapy, Lancet 1: 447, 1950. 11. Strong, J. A.: Serum potassium deficiency during treatment with sodium P.A.S. and liquorice extract, Brit. M. J. 2: 998, 1951. 12. Rousak, N. J.: Fatal hypokalaemic alkalosis with tetany during liquorice and P.A.S. therapy, Brit. M. J. 1: 360, 1952.
saliva f r o m 2 of the p a t i e n t s J T h e sixth subject h a d a diminished concentration of I g A only in saliva. 2 T h e karyotypes of p e r i p h e r a l leukocytes a n d skin fibroblast cells of 3 subjects showed a ring No. 18 chromosome. 1-s Apparently IgA i m m u n o g l o b u l l n anomalies in patients with deleted arms of a p a i r No. 18 c h r o m o s o m e have been observed previously only on 3 occasionsa-~; of these, 2 were of the long a n d 1 of the short arm. W e are r e p o r t i n g the case of an 18-year-old Caucasian girl with a m e n t a l age of 9 years who presented the nonspecific p h e n o t y p e characteristics (growth retardation, facial dysmorphia, hypertelorlsm, ptelzygium colli) noted in p r i o r cases w i t h deletion of the short a r m f r o m a chromosome of p a i r No. 18. H e r chromosome a n o m a l y has been confirmed by leukocyte a n d fibroblast culture. Chromosomes of the parents were f o u n d to be normal. I t is of interest t h a t she laad an eczematoid rash on the face d u r i n g infancy, suffered f r o m frequent u p p e r respiratory infections, a n d has had recurrent n o n p a i n f u l
Volume 74 Number 6
Brie] clinical and laboratory observations
Table I. Serum immunoglobulin concentrations
Subject Proposita Mother Father
Immunoglobulin (mg. %)~ Gamma-G [ Gamma-A [ Garnma-M 1,600 2,000
<5 <5
500 300
900
300
420
1,200
370
180
~The immunodiffusion assay technique of Fahey arid McKelveys used gives normal values in milligrams per cent for adults of: IgG, 1,200 + 250 rag.; IgA, 120 "2_ 25 mg.; IgM, 100 + 20 rag.
swelling of the knees. Studies of the synovial fluid obtained by needle puncture of ,he knee showed no inflammatory, cells a n d a bacterial culture was negative. Serum immunoglobulin concentrations for the p r o b a n d and her parents are shown in Table I. I g A was not detected in the serum and' saliva of the patient. T h e I g A concentrations for the parents were normal. T h e mother and patient had a somewhat elevated I g M . Rectal mucosa of the patient was obtained by suction biopsy for immunocytochemical studies; there were plasma cells in the lamina propria, but the normal ratio of I g A to I g M positive plasma cells was reversed. T h e ,patient had blood group A, negative direct and indirect Coombs' test, positive anti-B isohemagglutinins at a titer of 1:128, and a negative Schick test. She received the usual childhood immunization for diphtheria. Routine peripheral blood cell counts, lupus erythematosus preparations, sedimentation rates, serum mucoproteins, antistreptolysin titer, rheumatoid factor, and antinuclear factor were all normal. T h e patient studied by Smith and D a e n t P had a deletion of the short arm of chromosome No. 18~ deficient !gA, and presented with " r h e u m a t o i d arthritis." W e could not establish such a diagnosis for the recurrent swelling of t h e knees observed in our patient. Ever/ though 0.14 to 0.42 per cent of clinically healthy individuals possess no detectabIe !gA, 6 and t h e serum and saliva IgA have been found normal in at least one patient with a ring No. 18 chromosome, ~ the immunoglobulin abnormalities, as well as
96 5
other isolated metabolic defects 7 observed in association with defects of chromosome No. 18, may be more than coincidental. T h e possibility that a gene locus for I g A c a n be shown on one a r m of pair No. 18 has become less simple in view of reports now available. 7 T h e genetic aspects of these cases will be discussed elsewhere. At this time we wish to emphasize the need for immunoglobulin studies of all patients with chromosomal deletions, and for chromosome studies of individuals with multiple congenital anomalies associated with immunologic disorders. The chromosome analyses of the parents were performed at the Joint Cytogenetics Service Laboratory, Rainier School. The serum immunoglobulin and blood analyses were performed at the Immunology Laboratories of the Department of Pediatrics, University of Washington, and in the clinical laboratory of Rainier School. The examination of the rectaI mucosa biopsy was performed by Dr. Shmuel Eidelman, Department of Medicine, University of Washington. The Laboratories of the King County Central Blood Bank, Seattle, performed the isohemagglutin titer. REFERENCES 1. Finley, S. C., Finley, W. H., Noto, T. A., Uchida, I. A., and Roddam R, F.: !gA absence associated with a ring-18 chromosome, Lancet 1: 1095, 1968. 2. Richards, B. W., and I{obbs, J. R.: IgA and ring-18 chromosome, Lancet 1: 1426, 1968. 3. Feingold, M, Schwartz, R . S., Atkins, L., A'nderson, R , Bartsocas, C. S., Page, D. L., arid Littlefield, J. W.: IgA deficiency associated with partial deletion of chromosome 18, J. Clin. Invest. 47: a42, 1968. (Abst.~ 4. Stewart, J., Go, S., Ellis, E., and Robinson, A.: IgA and partial deletions of chromosome18, Lancet 2: 779, 1968. 5. Smith, D., and Daentl, D.: Personal communication. 6. Hanson, L. A.: Aspects 6f the absence of the IgA system in immunologic deficiency diseases in man, in Bergsma, D., and Good, R. A., editors: Birth defects, original article series, vol. IV, No. I, New York, Feb., 1968, The National Foundation-March of Dimes, p. 292. 7. Fraser, G. R.: Partial monosomy 18, Lancet 1: 664, t964, 8. fahey, J.C., and McKelyey, E. M.: Quantitative determination of serum immunoglobulins in antibody agar plates, J. Immunol. 94: 84, 1965.