which is increased on the surface of cystic fibrosis epithelial cells. J Clin 1991;338:725 Invest. 1993;92:1875 24. Burns JL, Stapp JR, Yim DL, Emerson J, Ramsey BW, Clausen CR. 17. Woods DE, Bass JA, Johanson JWG, Straus DC. Role of adherence in the Microbiology of cystic fibrosis sputum from US centers. Clin Infect Dis. pathogenesis of Pseudomonas aeruginosa lung in cystic fibrosis In press patients. Infect Immunol. 1980;30:694 25. Zabner J, Couture LA, Gregory RJ, Graham SM, Smith AE, Welsh MJ. 18. Speert DP, Campbell ME, Farmer SW, Volpel K, Joffe AM, Parancych Adenovirus-mediated gene transfer transiently corrects the chloride W. Use of a pilin gene probe to study molecular epidemiology of transport defect in nasal epithelia of patients with cystic fibrosis. Cell. Pseudomonas aeruginosa. J Clin Microbiol. 1989;27:2589 1993;75:207 19. Lam J, Chan R, Lam K, Costerton JW. Production of mucoid microcolo- 26. Crystal RG, McElvaney NG, Rosenfeld MA, et al. Administration of an nies by Pseudomonas aeruginosa within infected lungs in cystic fibrosis. adenovirus containing the human CFTR cDNA to the respiratory tract Infect Immunol. 1980;28:546 of individuals with cystic fibrosis. Nat Genet. 1994;8:42 20. Baltimore RS, Mitchell M. Immunologic investigations of mucoid 27. Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care strains of Pseudomonas aeruginosa: comparison of susceptibility to opso- Med. 1996;154:1229 nic in mucoid and nonmucoid strains. J Infect Dis. 1980;141:238 28. Ramsey BW, Dorkin HL, Eisenberg JD, et al. Efficacy of aerosolized 21. Cabral DA, Loh BA, Speert DP. Mucoid Pseudomonas aeruginosa resists tobramycin in patients with cystic fibrosis. N Engl J Med. 1993;328:1740 nonopsonic by human neutrophils and . Pe- 29. Ramsey BW, Burns J, Smith A. Safety and efficacy of tobramycin solu- diatr Res. 1987;22:429 tion for inhalation in patients with cystic fibrosis: the results of two 22. Konstan MW, Berger M. Infection and inflammation of the lung in phase III placebo controlled clinical trials. Pediatr Pulmonol. 1997;(suppl cystic fibrosis. In: Davis PB, ed. Cystic Fibrosis. New York, NY: Marcel 14):137 Dekker; 1993:219–276 30. di Sant’Agnese PA, Darling RC, Perera GA, Shea E. Abnormal electro- 23. Valerius NH, Koch C, Hoiby N. Prevention of chronic Pseudomonas lyte composition of sweat in cystic fibrosis of the pancreas. Pediatrics. aeruginosa colonisation in cystic fibrosis by early treatment. Lancet. 1953;12:549

COMMENTARY

Agammaglobulinemia, by Col. Ogden C. Bruton, MC, USA, Pediatrics, 1952;9:722–728

Comments by Rebecca H. Buckley, MD

ABSTRACT OF ORIGINAL ARTICLE. A hitherto un- In the Discussion, [the author] concluded that there recognized entity manifested by complete absence of was a cause-and-effect relationship between the absence gamma globulin with otherwise normal serum proteins of gamma globulin and the repeated , based on and recurrent pneumococcal sepsis is described in an the child’s dramatic improvement after beginning 8-year-old male. The patient appeared to be normal in gamma globulin therapy. [The author] proposed two pos- other respects and, after extensive study, no structural or sible causes–congenital or acquired. While [he] felt that functional change could be demonstrated in any body the patient’s good health for the first 4.5 years of life system. He was unable to produce antibody to the pneu- argued against a congenital cause, the persistence of the mococcus with the four antigenic substances used; a pos- defect supported it. itive Schick test persisted despite numerous attempts to reverse it with diphtheria toxoid. No antibody could be demonstrated following administration of typhoid vac- COMMENTARY cine in the usual manner, and his serum was negative for his article is seminal, because it reports the complement-fixing of epidemic parotitis after very first described human host defect.1 Before he experienced a typical clinical picture of that disease. that time, it had always been assumed that Gamma globulin could be demonstrated in his serum T infections were attributable to excessive exposure to after concentrated immune human serum globulin was infectious agents or to changing or unusual proper- administered subcutaneously, and its gradual disappear- ties of the organisms involved. This recognition of ance could be followed by electrophoretic analysis over a the first human primary disease period of approximately six weeks. Concurrently, and 1 following administration of human gamma globulin (3.2 4 ⁄2 decades ago set the stage for an exponential gm. gamma globulin) at monthly intervals, he had been increase in information about the functions of the free of pneumococcal sepsis for more than a year, various components of the . Since whereas he had experienced clinical sepsis at least 19 then, Ͼ70 primary immunodeficiency disorders have times in the previous four years. Eight different types of been recognized,2 and this has obviously had a pro- pneumococci had been recovered from blood cultures found effect on the health care of children. during 10 different episodes of sepsis. The condition described in this landmark article is now referred to as Bruton’s or X-linked agamma- globulinemia (XLA). Boys with this condition remain From the Departments of Pediatrics and Immunology, Duke University well during the first few months of life by virtue of Medical Center, Durham, North Carolina. maternally transmitted IgG antibodies. Thereafter, Received for publication Mar 19, 1998; accepted Mar 19, 1998. they repeatedly acquire infections with extracellular Address correspondence to: Rebecca H. Buckley, MD, Duke University Medical Center, Box 2898, Durham, NC 27710. pyogenic organisms such as pneumococci, strepto- PEDIATRICS (ISSN 0031 4005). Copyright © 1998 by the American Acad- cocci, and haemophilus unless given prophylactic emy of Pediatrics. or gammaglobulin therapy. Chronic fun-

Downloaded from www.aappublications.org/news by guest on October 1, 2021 SUPPLEMENT 213 gal infections are not usually present, and Pneumo- Btk protein, enzymatic activity, or mRNA also have cystis carinii pneumonia rarely occurs unless there is permitted identification of X-linked inheritance in an associated . Viral infections also are some boys with agammaglobulinemia with no fam- usually handled normally, with the notable excep- ily history.7 The fact that Btk also is expressed in cells tions of the hepatitis viruses and the enteroviruses.3 of myeloid lineage is of interest in light of the well- In addition to septic arthritis, patients with this con- known occurrence of intermittent neutropenia in dition may have joint inflammation similar to that boys with XLA, particularly at the onset of an acute seen in rheumatoid arthritis. Infections with Urea- infection.8 It is conceivable that Btk is only one of plasma urealyticum and viral agents such as echovi- several signaling molecules participating in myeloid ruses, coxsackie viruses, and adenovirus have been maturation and that neutropenia would be observed identified from joint fluid cultures of patients, even in XLA only when rapid production of such cells is on IVIG replacement therapy. These observations needed. XLA also has been reported in association suggest a primary role for antibody, particularly se- with growth hormone deficiency in nine cases.9 cretory IgA, in host defense against this group of viruses, because normal numbers and function A condition that resembles XLA phenotypically (ie, there is an absence of circulating B cells) occurs in have been present in all patients with XLA with 10 persistent enterovirus infections reported thus far. some females with agammaglobulinemic. The mo- Concentrations of immunoglobulins of all isotypes lecular basis for this autosomal recessive defect has ␮ are very low, and circulating B cells are usually been shown recently to be in the heavy absent. Pre-B cells are present in reduced numbers in chain gene on chromosome 14.10 The latter indicates the bone marrow. Tonsils usually are very small, and the fundamental necessity for expression of intact lymph nodes are rarely palpable because of absence membrane-bound ␮ chains for maturation. of germinal centers from these lymphoid tissues. Molecular Genetics of Other Primary Thymus architecture, including Hassall’s corpuscles, Immunodeficiency Diseases is normal, as are the thymus-dependent areas of A committee of the World Health Organization spleen and lymph nodes. has published several versions of a classification of In 1993, two groups of investigators independently primary immunodeficiency diseases over the past and almost simultaneously discovered the mutated 3 decades, with the most recent having been re- gene in XLA. Because XLA had been mapped pre- 2 cisely to position Xq22, one group successfully used ported in 1997. Until the past few years, there was the technique of positional cloning to identify an little insight into the fundamental problems under- abnormal gene in patients with this defect.4 For other lying a majority of these syndromes. Many have reasons, the second group had sought and found a B now been mapped to specific chromosomal loca- cell-specific tyrosine kinase important in murine B tions, and the fundamental biologic errors have signaling;5 the kinase was found to be been identified in an impressive number. As the encoded by a gene on the mouse X chromosome. fundamental causes of more of these disorders are When the human gene counterpart was cloned, it identified, it is likely that future classifications will was found to reside at Xq22, and the gene product be -based. was identical to that found by the first group. This Within the past 5 years, the molecular bases of four intracellular signaling tyrosine kinase has been X-linked immunodeficiency disorders have been dis- named Bruton tyrosine kinase (or Btk) in honor of Dr covered: XLA, X-linked immunodeficiency with Hy- Bruton. Btk is a member of the Tec family of cyto- per IgM, the Wiskott–Aldrich syndrome, and plasmic protein tyrosine kinases. It is expressed at X-linked severe combined immunodeficiency.2,7 The high levels in all B-lineage cells, including pre-B cells. abnormal gene in X-linked chronic granulomatous This kinase appears to be necessary for pre-B cell disease had been identified earlier, and the gene expansion and maturation into surface Ig-expressing encoding properdin (mutated in properdin defi- B cells, but probably has a role at all stages of B cell ciency) also has been cloned. The faulty gene in development. It has not been detected in any cells of X-linked lymphoproliferative disease has been local- T lineage, but it has been found in cells of the my- 5 ized to a specific site on the X chromosome but has eloid series. Thus far, all males with known XLA (by not yet been identified.2,7 family history) have had low or undetectable Btk Autosomal recessive for mRNA and kinase activity. To date Ͼ250 different which the molecular bases have been discovered mutations in the human Btk gene have been recog- nized.6 These have encompassed most parts of the include leukocyte adhesion deficiency type 1; coding portions of the gene, and there has not been adenosine deaminase deficiency; purine nucleo- any clear correlation between the location of the side phosphorylase deficiency; ataxia–telangiecta- 11 12 mutation and the clinical phenotype.6 sia; DiGeorge syndrome; MHC antigen deficien- 13 14 ␣ ␣ Female carriers of XLA can be identified by the cy; ZAP-70 deficiency;, IL-2 receptor (IL2R ) 15 ␥ finding of nonrandom X chromosome inactivation in chain deficiency; Jak3 deficiency; and interferon their B cells or by the detection of the mutated gene receptor deficiency.16 The discovery and cloning of (if known in the family).7 Prenatal diagnosis of af- the genes for these diseases have obvious implica- fected or nonaffected male fetuses also has been ac- tions for the potential of . The rapid- complished by detection of the mutated gene in cho- ity of these advances suggests that there will soon rionic villous or amniocentesis samples. Studies of be many more to come.

214 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on October 1, 2021 REFERENCES X-linked agammaglobulinemia with growth hormone deficiency. J Pe- diatr. 1991;119:392–397 1. Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9:722–728 10. Yel L, Minegishi Y, Coustan-Smith E, et al. Mutations in the mu heavy 2. WHO Scientific Group. Primary immunodeficiency diseases. Clin Exp chain gene in patients with agammaglobulinemia. N Engl J Med. 1996; Immunol. 1997;109(suppl 1):1–28 335:1486–1493 3. Wilfert CM, Buckley RH, Mohanakumar T, et al. Persistent and fatal 11. Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia telangiectasia central nervous system Echovirus infections in patients with agamma- gene with a product similar to PI-3 kinase. Science. 1995;268:1749–1753 globulinemia. N Engl J Med. 1977;296:1485–1489 12. Budarf ML, Collins J, Gong W, et al. Cloning a balanced translocation 4. Vetrie D, Vorechovsky I, Sideras P, et al. The gene involved in X-linked associated with DiGeorge syndrome and identification of a disrupted agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993;361:226–233 candidate gene. Nat Genet. 1995;10:269–278 5. Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression of a 13. Steimle V, Reith W, Mach B. Major histocompatibility complex class II b-cell cytoplasmic tyrosine kinase in human X-linked agammaglobu- deficiency: a disease of gene regulation. Adv Immunol. 1996;61:327–340 linemia. Cell. 1993;72:279–290 14. Elder ME, Lin D, Clever J, et al. Human severe combined immunode- 6. Vihinen M. BTKbase: XLA mutation registry. Immunol Today. 1996;17: ficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science. 502–506 1994;264:1596–1599 7. Puck JM. Molecular and genetic basis of X-linked immunodeficiency 15. Buckley RH, Schiff RI, Schiff SE, et al. Human severe combined immu- disorders. J Clin Immunol. 1994;14:81–89 nodeficiency (SCID): genetic, phenotypic and functional diversity in 108 8. Buckley RH, Rowlands DR. Allergy rounds: agammaglobulinemia, neu- infants. J Pediatr. 1997;130:378–387 tropenia, fever and abdominal pain. J Allergy Clin Immunol. 1973;51: 16. Jouanguy E, Altare F, Lamhamedi S, et al. Interferon-gamma-receptor 308–318 deficiency in an infant with fatal bacille Calmette-Guerin infection. 9. Conley ME, Burks AW, Herrod HG, Puck JM. Molecular analysis of N Engl J Med. 1996;335:1956–1961

COMMENTARY

Further Studies on the Treatment of Congenital Adrenal Hyperplasia with Cortisone: IV. Effect of Cortisone and Compound B in Infants With Disturbed Electrolyte Metabolism, by John F. Crigler Jr, MD, Samuel H. Silverman, MD, and Lawson Wilkins, MD, Pediatrics, 1952;10:397–413

Comments by Melvin M. Grumbach, MD, Edward B. Shaw Professor of Pediatrics

ABSTRACT OF ORIGINAL ARTICLE. Three infants suppressing secretions of the abnormal adrenals that with female pseudohermaphrodism attributable to the possibly cause salt loss actively, either from the pro- salt-losing form of congenital adrenal hyperplasia (CAH; duction of a specific “Na-losing” factor or from an adrenogenital syndrome) followed for 14 to 20 months antagonistic action of some of the steroids secreted by are described in detail. The first infant was admitted at the abnormal adrenal gland against those hormones the age of 7 weeks in adrenal crisis and studied inten- that normally regulate electrolyte metabolism. The sively during a 557-day hospitalization; the second, an studies in the three infants lead us to conclude that the infant 7 weeks of age, was hospitalized for 71⁄2 months; electrolyte disturbance in patients with the salt-losing and the third, a 9-week-old infant, was studied over a form of CAH is not merely simple deficiency of the 5-month period. adrenal salt hormone that appears to be associated The effects of cortisone and corticosterone on the sup- with the zona glomerulosa of the adrenal cortex. pression of the abnormal adrenals, as reflected in the The approach to the initial and long-term manage- urinary excretion of 17-ketosteroids (17-KS) and on the ment of infants with the salt-losing form of CAH de- electrolyte disturbance as manifested by changes in se- rived from the intensive study of these three infants is rum and urinary electrolytes and body weight, are de- described. The critical importance of the use of ade- scribed. Cortisone acetate produced more marked sup- quate NaCl and fluids by intravenous administration pression of the adrenal overactivity per milligram (as assessed by the urinary excretion of 17-KS), but less initially to repair the electrolyte and fluid deficiencies sodium retention than corticosterone. Both steroids, how- and the hemodynamic abnormalities without the use ever, improved the electrolyte abnormality significantly. of deoxycorticosterone acetate (DCA), if possible, in The possible mechanism of action of cortisone on the the initial treatment is emphasized because suppres- disturbed electrolyte metabolism is considered. We sion of the adrenal with cortisone seems to alter mate- suggest that cortisone can serve as a substitute for rially the requirement for DCA. The final combination deficient “Na-retaining hormone,” and/or it may act by of the maintenance dose of cortisone acetate (either intramuscularly or orally) after initial high-dose prim- ing, the amount of added NaCl, and the requirements From the Department of Pediatrics, University of California San Francisco, for DCA (as long-acting subcutaneous pellets prefera- San Francisco, California. bly), however, must be decided in each patient indi- Received for publication Mar 19, 1998; accepted Mar 19, 1998. vidually. Too high a dose of glucocorticoid resulted in Address correspondence to: Melvin M. Grumbach, MD, Department of impaired growth and cushingoid features as we de- Pediatrics, University of California San Francisco, San Francisco, CA 94143- 0434. scribed earlier; an inadequate dose of cortisone did not PEDIATRICS (ISSN 0031 4005). Copyright © 1998 by the American Acad- protect the infant from an adrenal crisis and was asso- emy of Pediatrics. ciated with rapid growth and skeletal maturation and

Downloaded from www.aappublications.org/news by guest on October 1, 2021 SUPPLEMENT 215 Agammaglobulinemia, by Col. Ogden C. Bruton, MC, USA,Pediatrics, 1952;9:722 −728 Rebecca H. Buckley Pediatrics 1998;102;213

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/102/Supplement_1/213 References This article cites 15 articles, 3 of which you can access for free at: http://pediatrics.aappublications.org/content/102/Supplement_1/213# BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Gene Therapy http://www.aappublications.org/cgi/collection/gene_therapy_sub Infectious Disease http://www.aappublications.org/cgi/collection/infectious_diseases_su b Pulmonology http://www.aappublications.org/cgi/collection/pulmonology_sub Immunologic Disorders http://www.aappublications.org/cgi/collection/immunologic_disorder s_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on October 1, 2021 Agammaglobulinemia, by Col. Ogden C. Bruton, MC, USA,Pediatrics, 1952;9:722 −728 Rebecca H. Buckley Pediatrics 1998;102;213

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/102/Supplement_1/213

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1998 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on October 1, 2021