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The Hyper Igm Arch Dis Child: First Published As 10.1136/Adc.71.2.150 on 1 August 1994

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The Hyper Igm Arch Dis Child: First Published As 10.1136/Adc.71.2.150 on 1 August 1994 150 Archives of Disease in Childhood 1994; 71: 150-152 Hypogammaglobulinaemia associated with normal or increased IgM (the hyper IgM Arch Dis Child: first published as 10.1136/adc.71.2.150 on 1 August 1994. Downloaded from syndrome): a case series review N Banatvala, J Davies, M Kanariou, S Strobel, R Levinsky, G Morgan Abstract Methods The clinical and immunological aspects of Sixteen children who presented to the 16 children with the syndrome of Hospital for Sick Children, London and the hypogammaglobulinaemia associated with 'Aghia Sophia' Children's Hospital between normal or increased IgM (the hyper IgM 1977 and 1991 with this syndrome are syndrome) and their responses to treat- reviewed. Clinical, genetic, and immunologi- ment are reviewed. Increased concentra- cal features and their response to treatment tions of IgM, neutropenia, and recurrent have been retrospectively studied. Four of infections could usually be controlled by these patients have been partially described antimicrobial and intravenous immuno- previously: patients 1 and 27 and patients 12 globulin treatment. Together with the and 13.8 bacterial infections characteristic of hypogammaglobulinaemia, these patients often developed opportunistic infections, Results including Pneumocystis carinii pneumo- FAMILY HISTORIES nia, often presenting in the first year of Fourteen of the 16 patients were boys and a life. The occurrence of sclerosing family history of immunodeficiency or cholangitis, neurological complications, unexplained death in childhood was suggested and neutropenia may be a result of in seven (table 1). Of the 16 patients, two sets an underlying cell mediated immune defi- of children were siblings (patients 1 and 2 and ciency, autoimmunity, or infection. 12 and 13) and the parents of patients 1 and 2 Despite a high incidence of opportunistic were first cousins. infections, immunological investigations did not show any abnormality of T cell function. These findings are discussed in CLINICAL FINDINGS the light of the recent demonstration that The age of presentation was between 1 month http://adc.bmj.com/ the lack of expression of a T lymphocyte and 10 years (mean 2 years) (table 1). Table 1 activation antigen is the molecular basis gives the medical histories before diagnosis. ofthe X linked form ofthe disorder. Most patients had symptoms consistent (Arch Dis Child 1994; 71: 150-152) with immunoglobulin deficiency, which included recurrent diarrhoea and vomiting, recurrent upper respiratory tract infections, Primary hypogammaglobulinaemia associated otitis media, and failure to thrive. Seven on September 28, 2021 by guest. Protected copyright. with normal or increased IgM ( the hyper IgM children developed Pneumocystis carinii syndrome) was first described in 1961.1 A pneumonia; in six P carinii pneumonia was the literature review fr6m 1992 documents only 67 presenting feature in the first year of life cases and describes considerable genetic and two of these children went on to have The Hospital for Sick heterogeneity within this group.2 Inheritance is a second episode. In addition, there was one Children, London usually X linked3 but in addition may be auto- case of cytomegalovirus pneumonitis. N Banatvala somal dominant4 and autosomal recessive.1 J Davies Additional features more consistent with S Strobel The gene for the X linked form has been cell mediated immunodeficiency were seen in R Levinsky cloned by several groups and encodes a T cell most patients. Severe neurological disease G Morgan activation molecule which is the ligand for occurred in five children, one (patient 14) 'Aghia Sophia' the CD40 molecule.56 X linked hyper IgM had cryptococcal meningitis which responded Children's Hospital, is distinguished from the more common to antifungal treatment. Two siblings had Athens, Greece X linked agammaglobulinaemia (Bruton's acute encephalitis. One (patient 1) recovered M Kanariou disease) by the presence of circulating with high doses of intravenous immuno- Host Defence and B lymphocytes and polyclonal IgM in X linked globulin and intraventricular immunoglobulin, Molecular hyper IgM syndrome, which are absent in but the other (patient 2) died from encephalitis Immunology Units, Institute of Child X linked agammaglobulinaemia. Like X linked associated with the isolation of papovavirus Health, 30 Guilford agammaglobulinaemia, hyper IgM syndrome from urine and adenovirus from stool samples. Street, London is regarded as a primary humoral defect, but Two children (patients 9 and 13) died from WC1N 1EH there are features that a disorders. S Strobel prominent suggest idiopathic progressive neurological R Levinsky T lymphocyte deficiency. We describe the Three patients developed sclerosing cholangi- G Morgan clinical and laboratory features of 16 children tis. Two died, one (patient 4) during liver Correspondence to: with hyper IgM syndrome and discuss the transplantation, the second (patient 16) from Dr Morgan. pathogenetic mechanisms implied by these hepatic failure. The disease is static in the third Accepted 15 April 1994 observations. (patient 15). Hypogammaglobulinaemia associated with normal or increased IgM (the hyper IgM syndrome): a case series review 151 Table 1 Age, sex, ethnicity, family history, and medical histories in the hyper IgM syndrome Age at Arch Dis Child: first published as 10.1136/adc.71.2.150 on 1 August 1994. Downloaded from Patient diagnosis Ethnic Family history and probable No (months) Sex origin inheritance pattern Medical history before diagnosis Status after diagnosis 1 40 M Indian Parents first cousins, brother of Cryptosporidiosis, combined adenovirus and Well patient 2, autosomal recessive echovirus meningoencephalitis, recurrent candidiasis, recurrent URTI 2 72 F Indian Parents first cousins, sister of Recurrent URTI, encephalitis, aspergillus Died from encephalitis patient 1, autosomal recessive pneumonia 3 3 M English Sporadic P carinii pneumonia, CMV pneumonitis, Well recurrent URTI, recurrent diarrhoea and vomiting 4 9 M English Sporadic P carinii pneumonia Cryptosporidiosis, cirrhosis secondary to scle- rosing cholangitis, second attack of P carinii pneumonia, died during liver transplanta- tion 5 19 M English Sporadic Recurrent chest infections, osteomyelitis, Recurrent chest infections, suspected tubercu- recurrent cutaneous abscesses lous osteomyelitis 6 10 M English Maternal uncle died at 6 Recurrent otitis media, red cell aplasia Neutropenia that responded to high doses of months, X linked intravenous immunoglobulin 7 7 M Pakistani Two brothers died at 1 year P carinii pneumonia, recurrent URTI, can- Ventilated for laryngotracheobronchitis, (pneumonia) and 2 years didiasis associated soft tissue pseudomonas infection (gastroenteritis), immunology uncertain, X linked 8 6 M English Sporadic P carinii pneumonia Pneumococcal pneumonia when not receiving treatment 9 30 F Indian Sporadic Recurrent cutaneous abscesses Died from progressive idiopathic neurological deterioration 10 6 M English Six male deaths over two gener- P carinii pneumonia Well ations: X linked 1 1 120 M Iraqi Sporadic Recurrent URTI, recurrent otitis media Well 12 48 M English Brother of patient 13, X linked Recurrent mouth ulcers, pericentric inver- Well or autosomal recessive sion of chromosome 7 13 5 M English Brother of patient 12, X linked P carinii pneumonia, giardiasis, developmen- Recurrent P carinii pneumonia, progressive or autosomal recessive tal delay with pericentric inversion of chro- idiopathic neurological deterioration, died mosome 7 aged 12 years 14 30 M Greek Sporadic Recurrent gastroenteritis, recurrent otitis Cryptococcal meningitis, erysipelas, neutrope- media and URTI, eczema nia responsive to granulocyte colony stimu- lating factor and high dose intravenous immunoglobulin 15 28 M Irish Sporadic Recurrent bacterial infections, sclerosing Well cholangitis 16 17 M Greek Sporadic P carinii pneumonia, recurrent chest infec- Death from sclerosing cholangitis tions and hepatosplenomegaly URTI=upper respiratory tract infection: CMV=cytomegalovirus. HAEMATOLOGY AND IMMUNOLOGY immunosuppression. Neutropenia resolved in Tables 2 and 3 give the haematological and all six patients once adequate doses of immunological indices. IgG and IgA were low immunoglobulin treatment had been given. in all 16 patients, but were rarely undetectable. Granulocyte colony stimulating factor was http://adc.bmj.com/ lgM was increased in seven patients and used in combination with intravenous normal in nine. Six patients were neutropenic immunoglobulin in one patient. High doses of at presentation with neutrophil counts less intravenous immunoglobulin were required to than 1 x 109/l. T lymphocyte enumeration prevent infection (up to 1 g/kg, every three showed a low CD4 count (O@5 X 109/i, patient weeks). All but one child (who developed red 11; table 3) in one patient and a low CD3 cell aplasia while receiving co-trimoxazole) are count (1-1x 109/l, patient 12, table 3) in being treated with prophylactic co-trimoxazole on September 28, 2021 by guest. Protected copyright. another. Phytohaemagglutinin stimulation was because of their susceptibility to P carinii normal in all patients. No autoantibody was pneumonia. detected in the six patients screened. Discussion RESPONSE TO TREATMENT This report significantly increases the docu- All patients received immunoglobulin replace- mented number of patients with this rare ment treatment, with a decrease in the disorder and highlights the underlying T cell frequency and severity of bacterial and
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