Dual novel variants in CD40 leading to hyper IgM syndrome: a case report of a school-aged female with new-onset recurrent pneumonia
Abstract
Introduction: Hyper IgM (HIGM) syndrome is an inborn error of immunity (IEI) that occurs due to defects in immunoglobulin class switch recombination (Ig-CSR). HIGM syndrome typically presents with recurrent infections in early childhood, and is often characterized on investigation with decreased IgG, IgA, and IgE titres, alongside normal or elevated IgM. A common cause of HIGM syndrome is a disruption to the CD40-CD40 ligand (CD40L) interaction that triggers Ig-CSR, of which variants in CD40 are much rarer than those in CD40L. We present a case of an 11-year-old female with HIGM syndrome caused by two novel variants of in the CD40 gene.
Aim: To describe a case report of an eleven-year-old female with HIGM syndrome presenting with recurrent pneumonia.
Methods: Data was collected retrospectively from the patient’s medical records. Laboratory investigations included quantitative immunoglobulins, quantitative B and T cell subsets, genetic testing using a primary immunodeficiency panel, and a functional assay for CD40 expression.
Results: The proband is an 11-year-old female, who presented with recurrent pneumonia, otitis, and septic arthritis. Investigations revealed neutropenia, low IgA, elevated IgM and normal IgG, along with absent vaccine responses. She was identified to harbour two novel variants in CD40: an intronic variant c.52-13A>G p.(?) and a missense variant c.466T>C p.(Ser156Pro). Functional assay indicated low expression of CD40 compared to healthy control, confirming the diagnosis of CD40 deficiency.
Conclusion: Class switch defects, such as CD40 deficiency, are rare but significant diagnoses within the spectrum of IEI. This case demonstrates that despite the absence of some clinical red flags for immunodeficiency in infancy, IEIs remain an important consideration in pediatric patients regardless of age. Increasing clinical awareness of IEI will lead to earlier diagnoses, initiation of appropriate treatment, and prevention of potential complications.
Statement of novelty: We describe a patient with a late presentation of hyper IgM syndrome due to two novel variants in the CD40 gene, thus expanding the spectrum of CD40 gene variants.
Get full access to this article
View all available purchase options and get full access to this article.
REFERENCES
Al-Saud B., Al-Jomaie M., Al-Ghonaium A., Al-Ahmari A., Al-Mousa H., Al-Muhsen S., Al-Seraihy A., Arnaout R., Elshorbagi S., Al-Dhekri H., and Ayas M. 2019. Haematopoietic stem cell transplant for hyper-IgM syndrome due to CD40 defects: a single-centre experience. Bone Marrow Transpl. 54: 63–67.
Al-Saud B.K., Al-Sum Z., Alassiri H., Al-Ghonaium A., Al-Muhsen S., Al-Dhekri H., Arnaout R., Alsmadi O., Borrero E., Abu-Staiteh A., Rawas F., Al-Mousa H., and Hawwari A. 2013. Clinical, immunological, and molecular characterization of hyper-IgM syndrome due to CD40 deficiency in eleven patients. J. Clin. Immunol. 33: 1325–1335.
Bousfiha A., Moundir A., Tangye S.G., Picard C., Jeddane L., Al-Herz W., Rundles C.C., Franco J.L., Holland S.M., Klein C., Morio T., Oksenhendler E., Puel A., Puck J., Seppänen M.R.J., Somech R., Su H.C., Sullivan K.E., Torgerson T.R., and Meyts I. 2022. The 2022 Update of IUIS phenotypical classification for human inborn errors of immunity. J. Clin. Immunol. 42: 1508–1520.
Cicalese M.P., Gerosa J., Baronio M., Montin D., Licciardi F., Soresina A., Dellepiane R.M., Miano M., Baselli L.A., Volpi S., Dufour C., Plebani A., Aiuti A., Lougaris V., and Fousteri G. 2018. Circulating follicular helper and follicular regulatory T cells are severely compromised in human CD40 deficiency: a case report. Front. Immunol. 9: 1761.
Gagnier J.J., Kienle G., Altman D.G., Moher D., Sox H., and Riley D., and the CARE Group. 2013. The CARE guidelines: consensus-based clinical case reporting guideline development. J. Med. Case Rep. 7: 223.
Ioannidis N.M., Rothstein J.H., Pejaver V., Middha S., McDonnell S.K., Baheti S., Musolf A., Li Q., Holzinger E., Karyadi D., Cannon-Albright L.A., Teerlink C.C., Stanford J.L., Isaacs W.B., Xu J., Cooney K.A., Lange E.M., Schleutker J., Carpten J.D., Powell I.J., Cussenot O., Cancel-Tassin G., Giles G.G., MacInnis R.J., Maier C., Hsieh C.-L., Wiklund F., Catalona W.J., Foulkes W.D., Mandal D., Eeles R.A., Kote-Jarai Z., Bustamante C.D., Schaid D.J., Hastie T., Ostrander E.A., Bailey-Wilson J.E., Radivojac P., Thibodeau S.N., Whittemore A.S., and Sieh W. 2016. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am. J. Hum. Genet. 99: 877–885.
Joshi A.Y., Iyer V.N., Hagan J.B., Sauver J.L., and St. Boyce T.G. 2009. Incidence and temporal trends of primary immunodeficiency: a population-based cohort study. Mayo Clin. Proc. 84: 16–22.
Kutukculer N., Moratto D., Aydinok Y., Lougaris V., Aksoylar S., Plebani A., Genel F., and Notarangelo L.D. 2003. Disseminated cryptosporidium infection in an infant with hyper-IgM syndrome caused by CD40 deficiency. J. Pediatr. 142: 194–196.
Leman R., Gaildrat P., Le Gac G., Ka C., Fichou Y., Audrezet M.-P., Caux-Moncoutier V., Caputo S.M., Boutry-Kryza N., Léone M., Mazoyer S., Bonnet-Dorion F., Sevenet N., Guillaud-Bataille M., Rouleau E., Bressac-de Paillerets B., Wappenschmidt B., Rossing M., Muller D., Bourdon V., Revillon F., Parsons M.T., Rousselin A., Davy G., Castelain G., Castéra L., Sokolowska J., Coulet F., Delnatte C., Férec C., Spurdle A.B., Martins A., Krieger S., and Houdayer C. 2018. Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort. Nucleic Acids Res. 46: 7913–7923.
Lougaris V., Badolato R., Ferrari S., and Plebani A. 2005. Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features. Immunol. Rev. 203: 48–66.
Murguia-Favela L., Sharfe N., Karanxha A., Bates A., Dadi H., Cimpean L., and Roifman C.M. 2017. CD40 deficiency: a unique adult patient with hyper immunoglobulin M syndrome and normal expression of CD40. LymphoSign J. 4: 70–76.
Pertea M., Lin X., and Salzberg S.L. 2001. GeneSplicer: a new computational method for splice site prediction. Nucleic Acids Res. 29: 1185–1190.
Reese M.G., Eeckman F.H., Kulp D., and Haussler D. 1997. Improved splice site detection in Genie. J. Comput. Biol. 4: 311–323.
Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J., Grody W.W., Hegde M., Lyon E., Spector E., Voelkerding K., and Rehm H.L., and ACMG Laboratory Quality Assurance Committee 2015. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17: 405–424.
Shapiro M.B. and Senapathy P. 1987. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 15: 7155–7174.
Stavnezer J., Guikema J.E.J., and Schrader C.E. 2008. Mechanism and regulation of class switch recombination. Annu. Rev. Immunol. 26: 261–292.
van Dongen J.J.M., van der Burg M., Kalina T., Perez-Andres M., Mejstrikova E., Vlkova M., Lopez-Granados E., Wentink M., Kienzler A.-K., Philippé J., Sousa A.E., van Zelm M.C., Blanco E., and Orfao A. 2019. EuroFlow-based flowcytometric diagnostic screening and classification of primary immunodeficiencies of the lymphoid system. Front. Immunol. 10: 1271.
Wehr C., Kivioja T., Schmitt C., Ferry B., Witte T., Eren E., Vlkova M., Hernandez M., Detkova D., Bos P.R., Poerksen G., von Bernuth H., Baumann U., Goldacker S., Gutenberger S., Schlesier M., Bergeron-van der Cruyssen F., Le Garff M., Debré P., Jacobs R., Jones J., Bateman E., Litzman J., van Hagen P.M., Plebani A., Schmidt R.E., Thon V., Quinti I., Espanol T., Webster A.D., Chapel H., Vihinen M., Oksenhendler E., Peter H.H., and Warnatz K. 2008. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood 111: 77–85.
Winkelstein J.A., Marino M.C., Ochs H., Fuleihan R., Scholl P.R., Geha R., Stiehm E.R., and Conley M.E. 2003. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore) 82: 373–384.
Yazdani R., Fekrvand S., Shahkarami S., Azizi G., Moazzami B., Abolhassani H., and Aghamohammadi A. 2019. The hyper IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management. Clin. Immunol. 198: 19–30. https://doi.org/10.1016/j.clim.2018.11.007
Yeo G. and Burge C.B. 2004. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J. Comput. Biol. 11: 377–394.
Information & Authors
Information
Published In
LymphoSign Journal
Volume 11 • Number 2 • June 2024
Pages: 32 - 37
History
Received: 26 January 2024
Accepted: 21 February 2024
Accepted manuscript online: 19 April 2024
Version of record online: 12 July 2024
Copyright
© 2024.
Authors
Metrics & Citations
Metrics
Other Metrics
Citations
Cite As
Jason ZXChen, AnahitaDehmoobad Sharifabadi, and Jenny Garkaby. 2024. Dual novel variants in CD40 leading to hyper IgM syndrome: a case report of a school-aged female with new-onset recurrent pneumonia. LymphoSign Journal.
11(2): 32-37. https://doi.org/10.14785/lymphosign-2024-0002
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
There are no citations for this item
View Options
Get Access
Login options
Check if you access through your login credentials or your institution to get full access on this article.
