De Novo mutation causing X-linked hyper-IgM syndrome: A family study in Taiwan

Yi-Chun Ma, Wen I. Lee, Shyh-Dar Shyur, Sheng-Chieh Lin, Li-Hsin Huang, Jiunn-Yi Wu

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

X-linked hyper-IgM syndrome (XHIM) is a rare primary immunodeficiency disorder caused by mutations of the gene encoding the CD40 ligand (CD40L). It is characterized by recurrent infections with markedly decreased serum IgG, IgA and IgE levels but normal or elevated IgM levels. We report the clinical manifestations and complete immune studies in the first family with molecularly proven XHIM in Taiwan. A 5-month-old boy presented with rapidly progressive pneumonia which responded poorly to antibiotics. High levels of IgM and very low levels of IgG, IgA, and IgE were noted in his plasma specimen: IgM, 128 mg/dl; IgG, 18 mg/dl; IgA, 4 mg/dl); IgE, 1 IU/ml. Whole blood flow cytometry when he was 21 months old showed that only a small percentage (0.48%) of his in vitro-activated CD4+ T cells expressed CD40L. When he was 3 years old, repeated flow cytometry showed essentially the same result (0.4%), compared with his father's CD40L expression of over 85%. The patient's mother had moderately decreased CD40L expression (74.4%). Hyper-IgM syndrome was confirmed by CD40L mutation analysis in the boy, which revealed a Lys 96 stop (nucleotide A307T) in exon 2 of CD40L, with a truncated protein resulting in the loss of the entire TNF domain. His mother was a carrier and apparently the individual in whom the mutation originated. Eleven other family members, including the patient's father, sister, and grandmother, and the mother's sisters and their children, all had normal results on CD40L mutation analysis. The patient has remained without significant bacterial infection on a regimen of monthly IVIG infusion and oral trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) prophylaxis, although he has had recurrent oral ulcers and neutropenia. Bone marrow transplantation is planned.
Original languageEnglish
Pages (from-to)53-59
Number of pages7
JournalAsian Pacific Journal of Allergy and Immunology
Volume23
Issue number1
Publication statusPublished - 2005
Externally publishedYes

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Type 1 Hyper-IgM Immunodeficiency Syndrome
CD40 Ligand
Taiwan
Mutation
Immunoglobulin A
Immunoglobulin E
Immunoglobulin M
Immunoglobulin G
Mothers
Fathers
Siblings
Hyper-IgM Immunodeficiency Syndrome
Flow Cytometry
Oral Ulcer
Pneumocystis Pneumonia
Intravenous Immunoglobulins
Sulfamethoxazole Drug Combination Trimethoprim
Neutropenia
Bone Marrow Transplantation
Bacterial Infections

Keywords

  • antibiotic agent
  • CD4 antigen
  • CD40 ligand
  • cotrimoxazole
  • immunoglobulin A
  • immunoglobulin E
  • immunoglobulin G
  • immunoglobulin M
  • tumor necrosis factor
  • adult
  • article
  • bacterial infection
  • blood sampling
  • bone marrow transplantation
  • case report
  • clinical feature
  • disease carrier
  • family study
  • female
  • flow cytometry
  • gene expression
  • gene mutation
  • human
  • hyperimmunoglobulinemia M
  • immune deficiency
  • immunoglobulin blood level
  • in vitro study
  • infant
  • male
  • mouth ulcer
  • mutational analysis
  • neutropenia
  • onset age
  • Pneumocystis pneumonia
  • pneumonia
  • protein domain
  • quantitative analysis
  • rare disease
  • recurrent infection
  • stop codon
  • T lymphocyte
  • Taiwan
  • X chromosome linkage
  • CD40 Ligand
  • Female
  • Genetic Diseases, X-Linked
  • Humans
  • Hypergammaglobulinemia
  • Immunoglobulin M
  • Infant
  • Killer Cells, Natural
  • Male
  • Mutation
  • Pneumonia

Cite this

De Novo mutation causing X-linked hyper-IgM syndrome: A family study in Taiwan. / Ma, Yi-Chun; Lee, Wen I.; Shyur, Shyh-Dar; Lin, Sheng-Chieh; Huang, Li-Hsin; Wu, Jiunn-Yi.

In: Asian Pacific Journal of Allergy and Immunology, Vol. 23, No. 1, 2005, p. 53-59.

Research output: Contribution to journalArticle

Ma, Yi-Chun ; Lee, Wen I. ; Shyur, Shyh-Dar ; Lin, Sheng-Chieh ; Huang, Li-Hsin ; Wu, Jiunn-Yi. / De Novo mutation causing X-linked hyper-IgM syndrome: A family study in Taiwan. In: Asian Pacific Journal of Allergy and Immunology. 2005 ; Vol. 23, No. 1. pp. 53-59.
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abstract = "X-linked hyper-IgM syndrome (XHIM) is a rare primary immunodeficiency disorder caused by mutations of the gene encoding the CD40 ligand (CD40L). It is characterized by recurrent infections with markedly decreased serum IgG, IgA and IgE levels but normal or elevated IgM levels. We report the clinical manifestations and complete immune studies in the first family with molecularly proven XHIM in Taiwan. A 5-month-old boy presented with rapidly progressive pneumonia which responded poorly to antibiotics. High levels of IgM and very low levels of IgG, IgA, and IgE were noted in his plasma specimen: IgM, 128 mg/dl; IgG, 18 mg/dl; IgA, 4 mg/dl); IgE, 1 IU/ml. Whole blood flow cytometry when he was 21 months old showed that only a small percentage (0.48{\%}) of his in vitro-activated CD4+ T cells expressed CD40L. When he was 3 years old, repeated flow cytometry showed essentially the same result (0.4{\%}), compared with his father's CD40L expression of over 85{\%}. The patient's mother had moderately decreased CD40L expression (74.4{\%}). Hyper-IgM syndrome was confirmed by CD40L mutation analysis in the boy, which revealed a Lys 96 stop (nucleotide A307T) in exon 2 of CD40L, with a truncated protein resulting in the loss of the entire TNF domain. His mother was a carrier and apparently the individual in whom the mutation originated. Eleven other family members, including the patient's father, sister, and grandmother, and the mother's sisters and their children, all had normal results on CD40L mutation analysis. The patient has remained without significant bacterial infection on a regimen of monthly IVIG infusion and oral trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) prophylaxis, although he has had recurrent oral ulcers and neutropenia. Bone marrow transplantation is planned.",
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author = "Yi-Chun Ma and Lee, {Wen I.} and Shyh-Dar Shyur and Sheng-Chieh Lin and Li-Hsin Huang and Jiunn-Yi Wu",
note = "被引用次數:8 Export Date: 7 April 2016 CODEN: APJIE 通訊地址: Shyur, S.-D.; Department of Pediatrics, Division of Pediatric Allergy and Immunology, Mackay Memorial Hospital, Taipei, Taiwan; 電子郵件: abc1016@ms2.mmh.org.tw 化學物質/CAS: CD40 ligand, 226713-27-5; cotrimoxazole, 8064-90-2; immunoglobulin E, 37341-29-0; immunoglobulin G, 97794-27-9; immunoglobulin M, 9007-85-6; CD40 Ligand, 147205-72-9; Immunoglobulin M 參考文獻: Fuleihan, R.L., Hyper-IgM syndrome (1998) Encyclopedia of Immunology, pp. 1166-1169. , Delves PJ, Roitt IM, eds. 2nd ed. London, Academic Press; Ochs, H.D., Stieham, E.R., Winkelstein, J.A., The hyper-IgM syndrome (2004) Immunologic Disorders in Infants and Children, pp. 380-390. , Stieham ER, Ochs HD, Winkelstein JA, eds. 5th ed. Philadelphia, Elsevier Inc; Santadusit, S., Visitsunthon, N., Ochs, H.D., Vichyanond, P., X-linked hyper-IgM syndrome: A report of the first case in Thailand with confirmed mutation of CD40 ligand gene (2000) Asian Pac. J. Allergy Immunol., 18, pp. 165-168; Ramesh, N., Geha, R.S., Notarangelo, L.D., CD40 ligand and the hyper-IgM syndrome (1999) Primary Immunodeficiency Disease - A Molecular and Genetic Approach, pp. 233-245. , HD, Smith CIE, Puck JM, eds. New York, Oxford; Basile, G.D.S., Tabone, M.D., Durandy, A., CD40 ligand expression deficiency in a female carrier of the X-linked hyper-IgM syndrome as a result of X chromosome lyonization (1999) Eur. J. Immunol., 29, pp. 367-373; Lee, W.I., Torgerson, T.R., Schumacher, M.J., Yel, L., Zhu, Q., Ochs, H.D., Molecular Analysis of a Large Cohort of Patients with the Hyper IgM Syndrome (HIGM) (2005) Blood, 105, pp. 1881-1890; Hollenbaugh, D., Grosmaire, L.S., Kullas, C.D., The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: Expression of a soluble form of gp39 with B cell co-stimulatory activity (1992) EMBO J., 11, pp. 4313-4321; Callard, R.E., Smith, S.H., Herbert, J., CD40 ligand expression and B cell function in agammaglobulinemia with normal or elevated levels of IgM (HIM). Comparison of X-linked, autosomal recessive and non-X-linked forms of the disease, and obligate carrier (1994) J. Immunol., 153, pp. 3295-3306; Miller, M.L., Algayed, I.A., Yogev, R., chou, P.M., Scholl, P.R., Pachman, L.M., Atypical Pneumocystis carinii pneumonia in a child with hyper-IgM syndrome (1998) Pediatr. Pathol. Lab. Med., 18, pp. 71-78; Fuleihan, R.L., Hyper-IgM syndrome: The other side of the coin (2001) Curr. Opin. Pediatr., 13, pp. 528-532; Levy, J., Espanol-Boren, T., Thomas, C., Clinical spectrum of X-linked hyper-IgM syndrome (1997) J. Pediatr., 131, pp. 47-54; Cham, B., Bonilla, M.A., Winkelstein, J., Neutropenia associated with primary immunodeficiency syndrome (2002) Semin. Hematol., 39, pp. 107-112; Inwald, D.P., Peters, M.J., Walshe, D., Jones, A., Davies, E.G., Klein, N.J., Absence of platelet CD40L identifies patients with X-linked hyper-IgM syndrome (2000) Clin. Exp. Immunol., 120, pp. 499-502; O'Gorman, M.R., Zaas, D., Paniagua, M., Corrochano, V., Scholl, P.R., Pachman, L.M., Development of a rapid whole blood flow cytometry procedure for the diagnosis of X-linked hyper-IgM syndrome patients and carriers (1997) Clin. Immunol. Immunopathol., 85, pp. 172-181; Bonilla, F.A., Geha, R.S., Primary immunodeficiency diseases (2003) J. Allergy Clin. Immunol., 111, pp. s571-s581; Winkelstein, J.A., Marino, M.C., Ochs, H., The X-linked hyper-IgM syndrome: Clinical and immunologic features of 79 patients (2003) Medicine, 82, pp. 373-384; Khawaja, K., Gennery, A.R., Flood, T.J., Abinun, M., Cant, A.J., Bone marrow transplantation for CD40 ligand deficiency: A single center experience (2001) Arch. Dis. Child, 84, pp. 508-511; Tomizawa, D., Imai, K., Ito, S., Allogeneic hematopoietic stem cell transplantation for seven children with X-linked hyper-IgM syndrome: A single center experience (2004) Am. J. Hematol., 76, pp. 33-39; Ostenstad, B., Giliani, S., Mellbye, O.J., Nilsen, B.R., Abrahamsen, T., A boy with X-linked hyper-IgM syndrome and natural killer cell deficiency (1997) Clin. Exp. Immunol., 107, pp. 230-234; Robert, L., T-Cell Immunodeficiency Disorders (2001) Medical Immunology, pp. 317-318. , Tristram G., Daniel P, Abba I, John B, eds. 10th ed. United States, Appleton & Lange",
year = "2005",
language = "English",
volume = "23",
pages = "53--59",
journal = "Asian Pacific Journal of Allergy and Immunology",
issn = "0125-877X",
publisher = "The Allergy and Immunology Society of Thailand",
number = "1",

}

TY - JOUR

T1 - De Novo mutation causing X-linked hyper-IgM syndrome: A family study in Taiwan

AU - Ma, Yi-Chun

AU - Lee, Wen I.

AU - Shyur, Shyh-Dar

AU - Lin, Sheng-Chieh

AU - Huang, Li-Hsin

AU - Wu, Jiunn-Yi

N1 - 被引用次數:8 Export Date: 7 April 2016 CODEN: APJIE 通訊地址: Shyur, S.-D.; Department of Pediatrics, Division of Pediatric Allergy and Immunology, Mackay Memorial Hospital, Taipei, Taiwan; 電子郵件: abc1016@ms2.mmh.org.tw 化學物質/CAS: CD40 ligand, 226713-27-5; cotrimoxazole, 8064-90-2; immunoglobulin E, 37341-29-0; immunoglobulin G, 97794-27-9; immunoglobulin M, 9007-85-6; CD40 Ligand, 147205-72-9; Immunoglobulin M 參考文獻: Fuleihan, R.L., Hyper-IgM syndrome (1998) Encyclopedia of Immunology, pp. 1166-1169. , Delves PJ, Roitt IM, eds. 2nd ed. London, Academic Press; Ochs, H.D., Stieham, E.R., Winkelstein, J.A., The hyper-IgM syndrome (2004) Immunologic Disorders in Infants and Children, pp. 380-390. , Stieham ER, Ochs HD, Winkelstein JA, eds. 5th ed. Philadelphia, Elsevier Inc; Santadusit, S., Visitsunthon, N., Ochs, H.D., Vichyanond, P., X-linked hyper-IgM syndrome: A report of the first case in Thailand with confirmed mutation of CD40 ligand gene (2000) Asian Pac. J. Allergy Immunol., 18, pp. 165-168; Ramesh, N., Geha, R.S., Notarangelo, L.D., CD40 ligand and the hyper-IgM syndrome (1999) Primary Immunodeficiency Disease - A Molecular and Genetic Approach, pp. 233-245. , HD, Smith CIE, Puck JM, eds. New York, Oxford; Basile, G.D.S., Tabone, M.D., Durandy, A., CD40 ligand expression deficiency in a female carrier of the X-linked hyper-IgM syndrome as a result of X chromosome lyonization (1999) Eur. J. Immunol., 29, pp. 367-373; Lee, W.I., Torgerson, T.R., Schumacher, M.J., Yel, L., Zhu, Q., Ochs, H.D., Molecular Analysis of a Large Cohort of Patients with the Hyper IgM Syndrome (HIGM) (2005) Blood, 105, pp. 1881-1890; Hollenbaugh, D., Grosmaire, L.S., Kullas, C.D., The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: Expression of a soluble form of gp39 with B cell co-stimulatory activity (1992) EMBO J., 11, pp. 4313-4321; Callard, R.E., Smith, S.H., Herbert, J., CD40 ligand expression and B cell function in agammaglobulinemia with normal or elevated levels of IgM (HIM). Comparison of X-linked, autosomal recessive and non-X-linked forms of the disease, and obligate carrier (1994) J. Immunol., 153, pp. 3295-3306; Miller, M.L., Algayed, I.A., Yogev, R., chou, P.M., Scholl, P.R., Pachman, L.M., Atypical Pneumocystis carinii pneumonia in a child with hyper-IgM syndrome (1998) Pediatr. Pathol. Lab. Med., 18, pp. 71-78; Fuleihan, R.L., Hyper-IgM syndrome: The other side of the coin (2001) Curr. Opin. Pediatr., 13, pp. 528-532; Levy, J., Espanol-Boren, T., Thomas, C., Clinical spectrum of X-linked hyper-IgM syndrome (1997) J. Pediatr., 131, pp. 47-54; Cham, B., Bonilla, M.A., Winkelstein, J., Neutropenia associated with primary immunodeficiency syndrome (2002) Semin. Hematol., 39, pp. 107-112; Inwald, D.P., Peters, M.J., Walshe, D., Jones, A., Davies, E.G., Klein, N.J., Absence of platelet CD40L identifies patients with X-linked hyper-IgM syndrome (2000) Clin. Exp. Immunol., 120, pp. 499-502; O'Gorman, M.R., Zaas, D., Paniagua, M., Corrochano, V., Scholl, P.R., Pachman, L.M., Development of a rapid whole blood flow cytometry procedure for the diagnosis of X-linked hyper-IgM syndrome patients and carriers (1997) Clin. Immunol. Immunopathol., 85, pp. 172-181; Bonilla, F.A., Geha, R.S., Primary immunodeficiency diseases (2003) J. Allergy Clin. Immunol., 111, pp. s571-s581; Winkelstein, J.A., Marino, M.C., Ochs, H., The X-linked hyper-IgM syndrome: Clinical and immunologic features of 79 patients (2003) Medicine, 82, pp. 373-384; Khawaja, K., Gennery, A.R., Flood, T.J., Abinun, M., Cant, A.J., Bone marrow transplantation for CD40 ligand deficiency: A single center experience (2001) Arch. Dis. Child, 84, pp. 508-511; Tomizawa, D., Imai, K., Ito, S., Allogeneic hematopoietic stem cell transplantation for seven children with X-linked hyper-IgM syndrome: A single center experience (2004) Am. J. Hematol., 76, pp. 33-39; Ostenstad, B., Giliani, S., Mellbye, O.J., Nilsen, B.R., Abrahamsen, T., A boy with X-linked hyper-IgM syndrome and natural killer cell deficiency (1997) Clin. Exp. Immunol., 107, pp. 230-234; Robert, L., T-Cell Immunodeficiency Disorders (2001) Medical Immunology, pp. 317-318. , Tristram G., Daniel P, Abba I, John B, eds. 10th ed. United States, Appleton & Lange

PY - 2005

Y1 - 2005

N2 - X-linked hyper-IgM syndrome (XHIM) is a rare primary immunodeficiency disorder caused by mutations of the gene encoding the CD40 ligand (CD40L). It is characterized by recurrent infections with markedly decreased serum IgG, IgA and IgE levels but normal or elevated IgM levels. We report the clinical manifestations and complete immune studies in the first family with molecularly proven XHIM in Taiwan. A 5-month-old boy presented with rapidly progressive pneumonia which responded poorly to antibiotics. High levels of IgM and very low levels of IgG, IgA, and IgE were noted in his plasma specimen: IgM, 128 mg/dl; IgG, 18 mg/dl; IgA, 4 mg/dl); IgE, 1 IU/ml. Whole blood flow cytometry when he was 21 months old showed that only a small percentage (0.48%) of his in vitro-activated CD4+ T cells expressed CD40L. When he was 3 years old, repeated flow cytometry showed essentially the same result (0.4%), compared with his father's CD40L expression of over 85%. The patient's mother had moderately decreased CD40L expression (74.4%). Hyper-IgM syndrome was confirmed by CD40L mutation analysis in the boy, which revealed a Lys 96 stop (nucleotide A307T) in exon 2 of CD40L, with a truncated protein resulting in the loss of the entire TNF domain. His mother was a carrier and apparently the individual in whom the mutation originated. Eleven other family members, including the patient's father, sister, and grandmother, and the mother's sisters and their children, all had normal results on CD40L mutation analysis. The patient has remained without significant bacterial infection on a regimen of monthly IVIG infusion and oral trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) prophylaxis, although he has had recurrent oral ulcers and neutropenia. Bone marrow transplantation is planned.

AB - X-linked hyper-IgM syndrome (XHIM) is a rare primary immunodeficiency disorder caused by mutations of the gene encoding the CD40 ligand (CD40L). It is characterized by recurrent infections with markedly decreased serum IgG, IgA and IgE levels but normal or elevated IgM levels. We report the clinical manifestations and complete immune studies in the first family with molecularly proven XHIM in Taiwan. A 5-month-old boy presented with rapidly progressive pneumonia which responded poorly to antibiotics. High levels of IgM and very low levels of IgG, IgA, and IgE were noted in his plasma specimen: IgM, 128 mg/dl; IgG, 18 mg/dl; IgA, 4 mg/dl); IgE, 1 IU/ml. Whole blood flow cytometry when he was 21 months old showed that only a small percentage (0.48%) of his in vitro-activated CD4+ T cells expressed CD40L. When he was 3 years old, repeated flow cytometry showed essentially the same result (0.4%), compared with his father's CD40L expression of over 85%. The patient's mother had moderately decreased CD40L expression (74.4%). Hyper-IgM syndrome was confirmed by CD40L mutation analysis in the boy, which revealed a Lys 96 stop (nucleotide A307T) in exon 2 of CD40L, with a truncated protein resulting in the loss of the entire TNF domain. His mother was a carrier and apparently the individual in whom the mutation originated. Eleven other family members, including the patient's father, sister, and grandmother, and the mother's sisters and their children, all had normal results on CD40L mutation analysis. The patient has remained without significant bacterial infection on a regimen of monthly IVIG infusion and oral trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) prophylaxis, although he has had recurrent oral ulcers and neutropenia. Bone marrow transplantation is planned.

KW - antibiotic agent

KW - CD4 antigen

KW - CD40 ligand

KW - cotrimoxazole

KW - immunoglobulin A

KW - immunoglobulin E

KW - immunoglobulin G

KW - immunoglobulin M

KW - tumor necrosis factor

KW - adult

KW - article

KW - bacterial infection

KW - blood sampling

KW - bone marrow transplantation

KW - case report

KW - clinical feature

KW - disease carrier

KW - family study

KW - female

KW - flow cytometry

KW - gene expression

KW - gene mutation

KW - human

KW - hyperimmunoglobulinemia M

KW - immune deficiency

KW - immunoglobulin blood level

KW - in vitro study

KW - infant

KW - male

KW - mouth ulcer

KW - mutational analysis

KW - neutropenia

KW - onset age

KW - Pneumocystis pneumonia

KW - pneumonia

KW - protein domain

KW - quantitative analysis

KW - rare disease

KW - recurrent infection

KW - stop codon

KW - T lymphocyte

KW - Taiwan

KW - X chromosome linkage

KW - CD40 Ligand

KW - Female

KW - Genetic Diseases, X-Linked

KW - Humans

KW - Hypergammaglobulinemia

KW - Immunoglobulin M

KW - Infant

KW - Killer Cells, Natural

KW - Male

KW - Mutation

KW - Pneumonia

M3 - Article

VL - 23

SP - 53

EP - 59

JO - Asian Pacific Journal of Allergy and Immunology

JF - Asian Pacific Journal of Allergy and Immunology

SN - 0125-877X

IS - 1

ER -