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X-Linked Hyper Igm Syndrome: a Report of the First Case in Thailand with a Con­ Firmed Mutation of CD40 Ligand Gene

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X-Linked Hyper Igm Syndrome: a Report of the First Case in Thailand with a Con­ Firmed Mutation of CD40 Ligand Gene IASIAN PACIFIC JOURNAL OF ALLERGY AND IMMUNOLOGY (2000) 18: 165-168 CASE REPORT X-Linked Hyper IgM Syndrome: A Report of the First Case in Thailand with a Con­ firmed Mutation of CD40 Ligand Gene Sadhit Santadusit\ Nualanong Visitsunthon\ Hans D. OChS2 and Pakit Vichyanond1 X-linked hyper IgM syn­ SUMMARY X-linked hyper IgM (XHIM) syndrome is a rare congenital im­ drome is a rare congenital immuno­ munodeficiency disease caused by failure of B cell to isotype switch from deficiency syndrome caused by IgM to other classes of immunoglobulins in response to infections. Recent­ failure of B cells to isotype-switch ly, a molecular cloning of the gene responsible for the syndrome, the CD40L gene has been accomplished and the gene was successfully mapped to the from IgM -producing cells to cells long arm of X chromosome at the position Xq26. We, herein, report the first secreting other classes of immuno­ case of molecular proven XHIM in a Thai boy with a classic presentation and globulins in response to infections.] with a confirmed mutation of the CD40L gene. Case Report: A.S. was a 1 The syndrome is characterized by year 7 month old boy referred from Buriram Provincial Hospital for a work up and treatment for his recurrent infections consisted of chronic respirato­ absence or low of serum IgG, IgA ry tract infections with otitis media (since 6 months of age), chronic diar­ and IgE levels with a normal or rhea (since 9 months of age) and malnutrition (marasmus) secondary to his more frequently elevated serum longstanding illnesses. He was a product of a consanguineous marriage 2 IgM leve1. '· Affected patients are but without history of similar illness observed in his pedigree. Abnormal lab­ susceptible to recurrent sinopulmo­ oratory works up included IgG of 300 mg/dl, IgA 10 mg/dl, IgM 1,635 mg/dl, positive stool examinations for Cryptosporld/um, chronic colitis on radio­ nary infections, recurrent opportun­ graphic gastrointestinal follow through study, a positive acid fast bacillus istic infections, neutropenia, auto­ (AFB) stain of gastric aspirate and multiple positive bacterial cultures from immune disease, lymphoma and various body sources. His anti-HIV serology was negative. His hospital cancer of the liver, pancreas or bili­ course was significant for several bouts of infections of gastrointestinal, ary tree.2 The syndrome was first respiratory, and genitourinary systems. His treatment consisted of multiple 3 courses of antibiotics, antituberculous drugs and IVIG administrations. His described by Rosen et al. and by hospital course was complicated with feeding problem from an esophageal 4 Burtin et al. in 1961. Recently, a stricture requiring several esophageal dilatations. The analysis of CD40L molecular cloning of a gene respon­ gene revealed a point mutation of exon 5 (A619T) of the CD40L gene sible to the syndrome, the CD40 resulting in a stop codon confirming that indeed he had XHIM. He died with Pseudomonas septicemia during the waiting period for a bone marrow ligand gene, has been reported and transplantation from a cord-blood stem cell. the gene was successfully mapped to the long arm of X chromosome 2 at the position Xq26. ,6 The gene to isotype switch from IgM to the From The lDivision of Allergy and Immunol­ contains 5 exons and 4 introns and other class of immunolobulins.5 B ogy, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol Univer­ there are several mutation pat­ cells from patients with X-linked sity, Bangkok, Thailand, 2Department of IO tems. ,]] The CD40L expressed on hyper IgM syndrome lacking in the Pediatrics, University of Washington School activated T cells react with the expression of CD40L protein tran­ of Medicine, U.S.A. CD40 on B cells causing the latter script secrete high level of IgM and Correspondance: Pakit Vichyanond 166 SANTADUSIT, ET AL. low level ofIgG, IgA and IgE, We, discharge. Oral thrush was present. negative. Delayed type hypersen­ herein, reported the first case of Medium to coarse crepitations was sitivity test panel yielded positive classical X-linked hyper IgM syn­ heard on auscultation of both lungs. reaction only to Corynebacterium drome in Thailand with a con­ Liver was enlarged 3 cm below diphtheriae antigen. Immunoglob­ firmed mutation of his CD40L right costal margin. His routine lab­ ulin levels revealed IgG 300 mg/dl, gene. oratories consisting of complete IgA 10 mg/dl and IgM of 1,635 blood count, urine examination and mg/dl. Lymphocyte enumeration by CASE REPORT blood chemistry tests including F ACS revealed a B cell count of blood sugar, electrolytes and liver 2,077 cells/mm3, CD4+ T cells of 3 A.S. was a 1 year and 7 function tests were normal. Stool 1,850 cells/mm and CD8+ T cells 3 month old boy referred from Buri­ examinations revealed numerous of 1,063 cells/mm . DNA analysis ram Hospital (Northeastern Thai­ white blood cells with cyst of Cryp­ for the mutation of CD40 ligand land) to Siriraj Hospital in Bangkok tosporidium seen on 2 occasions. gene was performed by a previous­ for a work up and treatment for his Nevertheless stool culture failed to ly reported PCR and a single­ recurrent infections. He was a pro­ grow any pathogenic bacteria. His stranded, conformational polymor­ lo n duct of a consanguineous marriage. gastric aspirates for Mycobacterium phism (SSCP) technique. A Nevertheless, there was no family tuberculosis (TB) culture and a point mutation in the exon-5 (A history of similar illnesses observed polymerase chain reaction (PCR) 619 T, adenine at postion 619 being in his pedigree. He was born by utilizing a 16S rRNA-based pri­ substituted by thymidine) of his normal vaginal delivery with a birth mers12 were negative although acid CD40L gene was uncovered which weight of 2,500 gm. His vaccina­ fast staining for TB was positive resulted in a stop codon (Arg 200x) tion was up to date. His growth for only 1 bacillus. His serology for of the gene leading to nonproduc­ and development was normal until HIV (gel particle agglutination) was tion of the protein product. A 6 months of age when he began to develop recurrent respiratory tract infections and otitis media in both Table 1 Serial immunoglobulin levels of the patient, before and after ears along with chronic diarrhea. treatment with IVIG (Venoglobulin S, Alpha Therapeutics, He had been admitted at Buriram Co. Los Angeles, CA) Hospital on three occasions with pneumonia and severe diarrhea. On Date IgG IgA IgM Date and doses of IVIG arrival to Siriraj Hospital he was (mg/dl) (mgldl) (mgldl) febrile, cachectic and was in a state 19 March 98 405 36 1,665 27 March 98 (2.5 gm) of malnutrition due to his long­ 7 April 98 260 9 1,450 8 April 98 (2.5 gm) standing illnesses. His body weight 17 April 98 340 20 960 24 April 98 (5 gm) was 6.6 kg (below 3rd percentile) 12 May 98 365 5 570 3 June 98 (5 gm) and his height was 75 cm (below 18 June 98 660 13 425 7 July 98 (5 gm) 10th percentile). He was pale, weak 17 July 98 660 9 645 and dyspnic. Perforation of both ear drums was observed with foul smell introns nt 57 120 196 A619T 840 1822 aa 23 45 261 Fig. 1 An illustration showing CD40L gene with a site of mutation found· in the currently reported case of XHIM patient (point mutation in the exon 5[A 619 T]). X-LINKED HYPER IgM SYNDROME 167 definitive diagnosis is X-linked onset infections, usually within the tration of intravenous immunoglob­ hyper IgM syndrome was made. first year of life, upon a decline of ulins (IVIG) at appropriate dosages. During his admission, the patient maternally-derived antibodies. Al­ Administration of IVIG provide had several bouts of infections of though most infections are of adequate functional levels of IgG gastrointestinal, respiratory and bacterial origin, XHIM patients are and could also decrease serum level 18 22 genitourinary systems included also unusually susceptible to infec­ of IgM. - This may result from Candida septicemia and Pseudo­tions with opportunistic pathogens the reduction in the number of in­ monas urinary tract infections. He and often suffer from Pneumocystis fections and possibly involving the was treated with amphotericin B, carinii pneumonia and Crypto­regulatory effect of IgG molecules appropriate antibiotics and intra­ sporidium intestinal infection, on IgM production. Infections are venous immunoglobulins (5% conditions frequently observed with treated with specific antimicrobial Venoglobulin S, Alpha Therapeu­ T-cell immunodeficiencies but not administrations and neutropenia, if tics Co., Los Angeles, CA). After with other forms of hypogamma­ severe, can be treated with G-CSF.23 several courses of IVIG adminis­ globulinemia.8 IsekiC reported two Bone marrow transplantation can trations, his IgM level declined but siblings with hyper IgM syndrome cure XHIM and may be feasible if he continued to develop several whom the elder brother died with an HLA-matched sibling is avail­ recurrent infections (see Table I for disseminated Cryptococcosis but able. 24 Since our patient was the serial IgM levels). Cord blood stem the younger brother with CD40L only child in the family, a cord cell transplantation was contem­ gene analysis revealed a point blood stem cell transplantation plated but he expired from Pseudo­mutation (at nucleotide 475, trypto­ (from a planned sex-oriented, in monas septicemia before the pro­ phane [TGG] to cause a stop codon vitro fertilization) was contem­ cedure had been possible. [TAG]), survived with the normal plated. Unfortunately, the child did level of IgM after IVIG treatment. not survive his last severe septi­ Our patient had the typical char­ cemia from P.
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