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 Table of Contents  
CASE REPORT
Year : 2022  |  Volume : 13  |  Issue : 3  |  Page : 157-161

Transfusion-dependent anemia, and cytopenia secondary to parvovirus B19 infection as the first manifestation of X-linked hyper immunoglobulin M immunodeficiency syndrome in two male patients in their third decade of life


1 Princess Noorah Oncology Center, Dr. Soliman Fakeeh Hospital, Jeddah, Saudi Arabia
2 Princess Noorah Oncology Center, Jeddah, Saudi Arabia

Date of Submission29-Dec-2021
Date of Decision03-Mar-2022
Date of Acceptance10-May-2022
Date of Web Publication15-Sep-2022

Correspondence Address:
Dr. Hadel El-Haddad
Princess Noorah Oncology Center, Dr. Soliman Fakeeh Hospital, Jeddah
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_179_21

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  Abstract 

We describe two male patients with unique mutation of the CD40L gene, unlike the classic presentation of X-linked hyper immunoglobulin M immunodeficiency syndrome (XHIGM syndrome), both were healthy until presenting in their early twenties with a challenging symptomatic transfusion-dependent anemia, investigations confirmed XHIGM syndrome with concurrent chronic parvovirus infection.

Keywords: Anemia, parvovirus B19 infection, X-linked hyper immunoglobulin M immunodeficiency syndrome


How to cite this article:
El-Haddad H, Khan EA, El-Hemaidi I, Absi A. Transfusion-dependent anemia, and cytopenia secondary to parvovirus B19 infection as the first manifestation of X-linked hyper immunoglobulin M immunodeficiency syndrome in two male patients in their third decade of life. J Appl Hematol 2022;13:157-61

How to cite this URL:
El-Haddad H, Khan EA, El-Hemaidi I, Absi A. Transfusion-dependent anemia, and cytopenia secondary to parvovirus B19 infection as the first manifestation of X-linked hyper immunoglobulin M immunodeficiency syndrome in two male patients in their third decade of life. J Appl Hematol [serial online] 2022 [cited 2022 Sep 25];13:157-61. Available from: https://www.jahjournal.org/text.asp?2022/13/3/157/356091


  Introduction Top


Hyperimmunoglobulin M (HIGM) syndromes are a rare heterogeneous group of primary immunodeficiency disorders characterized by defects of immunoglobulin class switch recombination (CSR), with or without defects of somatic hypermutation (SHM).[1] This leads to low levels of immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E with normal or elevated levels of immunoglobulin M (IgM), and poor antibody function.[2] HIGM syndromes are genetically determined and are further subdivided into five subgroups based on the affected gene: CD40L deficiency X-linked hyper IgM immunodeficiency (XHIGM), activation-induced cytidine deaminase deficiency Hyper-IgM syndrome type 2, CD40 deficiency (HIGM3), HIGM4, and uracil N-glycosylase deficiency (HIGM5).

The most common form of HIGM is XHIGM, which is inherited in an X-linked manner, constitutes around 70% of the cases, with an estimated prevalence of 1:1,000,000 males,[3] and is caused by defects or deficiencies in CD40 ligand (CD154).[4] The disease-causing gene of XHIGM is CD40L, located on Xq26.3-Xq27.[5] CD40L is expressed primarily on activated CD4 + T cells, and interacts with CD40 expressed on B-cells, monocytes, macrophages, and dendritic cells. CD40L-CD40 interactions stimulate germinal center development of B-cells and are essential for the initiation of CSR and SHM.[1] These interactions also provide a co-stimulatory signal for T-cells, and lead to T-cell activation, and thus gene mutation leads to impairment of NK-and T-cell cytotoxicity, reduced or absent antigen-specific responses.[6] The combined T and B immunological defect is clearly illustrated by the susceptibility of patients with XHIGM to recurrent infections, autoimmune disorders, and malignancies.[4]

Half of the males develop symptoms by year 1 of age, and by year 4 of age, more than 90% are symptomatic.[6] The most common infections include recurrent upper and lower respiratory tract bacterial infections, opportunistic infections such as Pneumocystis jirovecii, fungal infections, and infectious or noninfectious protracted diarrhea that can lead to failure to thrive. Liver manifestations are prognostically important since chronic Cytomegalovirus and Cryptosporidium infection can lead to cirrhosis and cholangiocarcinoma.[7],[8] Other reported long-term complications are malignancies including hepatocarcinoma, neuroectodermal tumor of gastrointestinal tract and pancreas, as well as lymphoma, and autoimmune disorders such as inflammatory bowel disease and chronic arthritis. Hematologic manifestations of the syndrome include chronic neutropenia, anemia, and less commonly, thrombocytopenia. Neutropenia could be chronic, episodic, or cyclic, and is usually related to infections. Anemia when it occurs could be multifactorial and might be caused by one or more of the following factors: anemia of chronic disease, iron deficiency, rarely aplastic and/or Coombs-positive hemolysis.[9]

Human parvovirus B19 belongs to the Erythroparvovirus genus within the Parvoviridae family, and among this family, B19 is the only known parvovirus to be pathogenic to humans, clinical manifestations vary depending on the immunologic status of the affected host.[10] Parvovirus B19 infection in children with intact immune system is considered a common, self-limited disease and usually causes a mild febrile illness known as erythema infectiosum, whereas in adults it may cause arthritis. On the other hand, when immunocompromised patients get exposed to parvovirus B19, their immune system is unable to produce neutralizing antibodies, viremia persists and might lead to aplastic anemia and red blood cells aplasia which is usually seen in bone marrow biopsy in addition to the characteristic giant pronormoblast with viral inclusions.[11]

Rarely, certain CD40L mutations can result in mild phenotypes of XHIGM, these patients remain asymptomatic and undiagnosed with the disease manifesting only after exposure to parvovirus B19 infection.[11]


  Case Report Top


Case 1 is a 20-year-old male, who had completely normal childhood with no recurrent infections, presented with intermittent transfusion-dependent anemia of unknown cause despite extensive laboratory, radiological, infectious, and autoimmune investigations over 6 years. He had cyclic episodes of fever of unknown origin, weight loss, and night sweating accompanying the drop in hemoglobin with hepatosplenomegaly. Despite relatively prolonged periods of spontaneous remissions for almost 3 years, the patient relapsed and became progressively transfusion-dependent, needing transfusion almost every 2–3 weeks with thrombocytopenia and neutropenia [Table 1]. His initial bone marrow biopsy only showed evidence of ineffective erythropoiesis. A repeat bone marrow biopsy showed erythroid hyperplasia with maturation arrest. The immature erythroid precursors appear enlarged with occasional cytoplasmic blebbing and intranuclear viral inclusions [Figure 1]a. Frequent large, disintegrated cells are seen in the background with a large nucleus, pale chromatin, and eosinophilic nucleoli-like inclusions [Figure 1]b. The trephine biopsy revealed marked hypercellularity (~98%) with significant erythroid hyperplasia, reduced and left shifted granulopoiesis, and adequate megakaryopoiesis, and multiple giant pronormoblasts with eosinophilic inclusions and peripheral chromatin condensation [Figure 1]c.
Table 1: Investigations

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Figure 1: (a) Bone marrow aspirate showing erythroid precursors infected with parvovirus B19. (b) Large disintegrated erythroblasts with viral inclusions. (c) Giant erythroblasts with eosinophilic viral inclusions in bone marrow trephine biopsy

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Molecular myeloid panel showed low-level molecular abnormalities such as TP53, CEBPA, DNMT3A, and RUNX1, all found in <10%, those abnormalities resolved in a subsequent bone marrow biopsy.

In view of the bone marrow biopsy findings, parvovirus PCR was sent and it detected parvovirus genetic material [Table 1]. It is very unlikely for parvovirus B19 to cause such a picture in immunocompetent patients. The infection with parvovirus raised the possibility of an immunodeficiency, syndrome and led us to perform whole-exome sequencing, the result of which revealed the presence of a mutation in the CD40 ligand [Table 1]. He was born of a consanguineous marriage; his mother was negative for the same mutation with a negative maternal family history of a similar condition making his diagnosis as de novo XHIGM. Immunoglobulin levels were checked, and indeed, he had mildly elevated IgM 6.49 g/L, slightly low IgG 6.93 g/L and normal IgA.

The patient was treated with intravenous immunoglobulins (IVIG) course for parvovirus infection 1 g/m2 for 3 days, then continued monthly IVIG of 400 mg/kg. Shortly, after the IVIG infusion, he had a tremendous response in his complete blood count [Table 1] and complete normalization of the symptoms; with no further relapse or transfusion requirement over 10-year follow-up period.

Case 2 is a 22-year-old male, who also had a completely normal childhood, with a history of recurrent mild sinusitis and ear infections, presented with symptomatic anemia, and his hemoglobin has fallen to the low levels of 4.8 g/dl and neutropenia [Table 1]. He had hepatosplenomegaly, investigations ruled out hemolysis. He had severe reticulocytopenia, and viral serology was positive for parvovirus B19 IgM [Table 1]. Bone marrow examination showed characteristic features of parvovirus B19 just similar to the repeated bone marrow findings of case 1, based on our previous experience with the first patient, which raised the suspicion of immunodeficiency syndromes, whole-exome sequencing was sent and showed CD40L gene mutation [Table 1], immunoglobulins level showed mild elevation of IgM 3.7 g/L with low IgG 1.13 g/L and very low IgA <0.05 g/L. The patient required four transfusions and it took him around 30 days to become transfusion independent and another 60 days before normalization of his hemoglobin after receiving IVIG, he did not require any further blood transfusion and he is completely asymptomatic during the 1-year follow-up period. The patient was born of a consanguineous marriage. Family members testing are currently being conducted.


  Discussion Top


Classical XHIGM syndrome, presents in the early years of life, usually with different presentations mainly infectious, here we are reporting two unique patients with a rare presentation in regard to the age of presentation and to the presentation itself, as both presented with chronic anemia induced by parvovirus B19 infection manifested after the age of 20 years.

Case 1 had a milder phenotype, but there was a delay in the diagnosis, whereas case 2 had a severely low IgA level which explains recurrent sinusitis.

From a hematopathologic point of view despite the presence of typical morphological findings associated with parvovirus B19 infection in the first patient, this was masked by the marked hypercellularity and the associated dyserythropoiesis. The picture further complicated by the low-level myeloid molecular findings which diverted the differential diagnosis temporarily into the direction of myelodysplastic syndrome. Therefore, high index of suspicion should be practiced in such cases with unexplained nonhemolytic anemia or pancytopenia looking for any morphological feature of parvovirus B19.

A national registry in the United States was developed to provide clinical information on patients from 60 unrelated families with XHIGM syndrome. In this report, 50% were symptomatic within their 1st year of age and 90% by the age of 4 years.[3] Later, in life presentation has been reported; but has been mostly related to delayed diagnosis rather than delayed presentation.[12],[13]

Among the infections reported, pneumonia was the most prevalent, occurred in 80%, followed by upper respiratory tract infections which occurred in 49% including sinusitis and otitis media, and less frequently reported infections such as central nervous system infection, skin and soft-tissue infection, and osteomyelitis.[3]

Mild phenotypes of XHIGM are reported, usually associated with hypomorphic mutations of CD40 LG gene that do not eliminate protein function or expression, which results in milder phenotypes with atypical presentations, late-onset presentations, and less infections; making diagnosis more difficult.[13] There has not been in the literature a clear association between specific mutations and the clinical phenotype of the patients. In a retrospective analysis of 98 patients with XHIGM syndrome, only six had mild clinical phenotype, three out of the six patients presented with parvovirus B19-induced anemia, these three patients were completely asymptomatic until they developed chronic anemia caused by parvovirus B19 infection at the ages of 8, 14, and 17, respectively, and all three patients responded well to IVIG.[11] [Table 2] One of the three mild phenotype presenting with parvovirus infection-induced anemia had the same mutation expressed by case 2 which is a missense mutation Thr 254 Met, while case 1 had a stop gain mutation which is a very rare variant that has not been published yet in any of the genetic databases and classified as likely pathogenic based on American College of Medical Genetics recommendations.
Table 2: All published cases with X-linked hyper IgM immunodeficiency and parvovirus B19-induced anemia in adolescents and young adults

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The definitive therapy of the severe forms of this syndrome is bone marrow transplantation,[6],[14] but the benefit of transplant in our two patients is questionable given their mild phenotype and the absence of infections and other complications.

The role of IVIG in XHIGM is extrapolated from other immunodeficiency syndromes, it showed efficacy in decreasing lower respiratory tract and severe infections as it protects from severe infections caused by encapsulated bacteria as XHIGM patients are unable to form antibodies against these types of bacteria,[6] but it does not alter other clinical manifestations of the disease such as neutropenia, chronic diarrhea, liver disease, cholangitis, or other autoimmune manifestations, and it should be considered once the diagnosis is made, every 3–4 weeks intervals.


  Conclusion Top


We are reporting two cases of a late presentation of XHIGM. The similarity between the two cases is the occurrence of protracted anemia requiring blood transfusions from an unexpected relatively benign virus. The other point of similarity is their relatively late presentation probably indicating a milder form of disease from these two reported mutations. The occurrence of such a clinical scenario ought to raise a high index of suspicion of an underlying immunological disorder. We believe in the era of easily accessible molecular diagnostics more undiagnosed cases will come to light with the heightened awareness of this condition.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Davies EG, Thrasher AJ. Update on the hyper immunoglobulin M syndromes. Br J Haematol 2010;149:167-80.  Back to cited text no. 1
    
2.
Notarangelo LD, Duse M, Ugazio AG. Immunodeficiency with hyper-IgM (HIM). Immunodefic Rev 1992;3:101-21.  Back to cited text no. 2
    
3.
Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, et al. The X-linked hyper-IgM syndrome: Clinical and immunologic features of 79 patients. Medicine (Baltimore) 2003;82:373-84.  Back to cited text no. 3
    
4.
Tsai HY, Yu HH, Chien YH, Chu KH, Lau YL, Lee JH, et al. X-linked hyper-IgM syndrome with CD40LG mutation: Two case reports and literature review in Taiwanese patients. J Microbiol Immunol Infect 2015;48:113-8.  Back to cited text no. 4
    
5.
Wang LL, Zhou W, Zhao W, Tian ZQ, Wang WF, Wang XF, et al. Clinical features and genetic analysis of 20 Chinese patients with X-linked hyper-IgM syndrome. J Immunol Res 2014;2014:683160.  Back to cited text no. 5
    
6.
Dunn CP, de la Morena MT. X-linked hyper IgM syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Gripp KW, et al., editors. GeneReviews((R)). Seattle (WA): ???; 1993.  Back to cited text no. 6
    
7.
Hayward AR, Levy J, Facchetti F, Notarangelo L, Ochs HD, Etzioni A, et al. Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J Immunol 1997;158:977-83.  Back to cited text no. 7
    
8.
Rahman M, Chapel H, Chapman RW, Collier JD. Cholangiocarcinoma complicating secondary sclerosing cholangitis from cryptosporidiosis in an adult patient with CD40 ligand deficiency: Case report and review of the literature. Int Arch Allergy Immunol 2012;159:204-8.  Back to cited text no. 8
    
9.
Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr 1997;131:47-54.  Back to cited text no. 9
    
10.
Heegaard ED, Brown KE. Human parvovirus B19. Clin Microbiol Rev 2002;15:485-505.  Back to cited text no. 10
    
11.
Seyama K, Kobayashi R, Hasle H, Apter AJ, Rutledge JC, Rosen D, et al. Parvovirus B19-induced anemia as the presenting manifestation of X-linked hyper-IgM syndrome. J Infect Dis 1998;178:318-24.  Back to cited text no. 11
    
12.
Kutukculer N, Karaca NE, Aksu G, Aykut A, Pariltay E, Cogulu O. An X-linked hyper-IgM patient followed successfully for 23 years without hematopoietic stem cell transplantation. Case Reports Immunol 2018;2018:6897935.  Back to cited text no. 12
    
13.
França TT, Leite LF, Maximo TA, Lambert CG, Zurro NB, Forte WC, et al. A novel de novo mutation in the CD40 ligand gene in a patient with a mild X-linked hyper-IgM phenotype initially diagnosed as CVID: New aspects of old diseases. Front Pediatr 2018;6:130.  Back to cited text no. 13
    
14.
Thomas C, de Saint Basile G, Le Deist F, Theophile D, Benkerrou M, Haddad E, et al. Brief report: Correction of X-linked hyper-IgM syndrome by allogeneic bone marrow transplantation. N Engl J Med 1995;333:426-9.  Back to cited text no. 14
    


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    Tables

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