PEDIATRICS Vol. 120 No. 5 November 2007, pp. e1341-e1344 (doi:10.1542/peds.2007-0640)
EXPERIENCE & REASON |
Hematopoietic Stem Cell Transplantation Corrects the Immunologic Abnormalities Associated With Immunodeficiency–Centromeric Instability–Facial Dysmorphism Syndrome
a Paediatric Immunology Department, Newcastle General Hospital, Newcastle Upon Tyne, United Kingdom
b Department of Pediatrics, Bone Marrow Transplant Unit, Leiden University Medical Center, Leiden, Netherlands
c Department of Pediatrics, Nijmegen University Medical Center, Nijmegen, Netherlands
ABSTRACT
Immunodeficiency–centromeric instability–facial dysmorphism syndrome, characterized by variable immunodeficiency, centromeric instability, and facial anomalies caused by epigenetic dysregulation resulting in hypomethylation, is caused in many patients by mutations in DNMT3B, a DNA methyltransferase gene; associated infections are a major cause of serious sequelae and death. Hematopoietic stem cell transplantation may improve the clinical course in immunodeficiency–centromeric instability–facial dysmorphism syndrome. We report 3 unrelated patients with persistent infections and intestinal complications who successfully underwent hematopoietic stem cell transplantation after nonmyeloablative or myeloablative conditioning regimens using HLA-matched donors. In all cases, donor chimerism led to resolution of intestinal complications and infections, growth improvement, and correction of the immunodeficiency.
Key Words: immunodeficiency • centromeric instability • facial dysmorphism syndrome • hematopoietic stem cell transplantation • DNMT3B
Abbreviations: ICF, immunodeficiency–centromeric instability–facial dysmorphism • HSCT, hematopoietic stem cell transplantation • GvHD, graft-versus-host disease
Patients with immunodeficiency–centromeric instability–facial dysmorphism (ICF) syndrome show pericentromeric anomalies of chromosomes 1, 16, or 9 in mitogen-stimulated lymphocytes1 that consist of whole-arm deletions, multibranched chromosomes, translocations, isochromosomes, and decondensation of heterochromatic regions adjacent to the centromeres (juxtacentromeric heterochromatin) of these chromosomes as a result of hypomethylation2 (Fig 1). ICF syndrome is the only immunodeficiency described to be caused by epigenetic dysregulation rather than single gene defects critical for lymphoid development or signaling. Some patients have mutations in a DNA methyltransferase gene, DNMT3B,3 but others have no mutations identified.4 Clinical features include absent or low levels of serum immunoglobulins and facial anomalies.5,6 Primary ICF syndrome B cells have defective peripheral terminal B-cell differentiation, which contributes to agammaglobulinemia.7 Although hypogammaglobulinemia or agammaglobulinemia is most consistently described in patients with ICF syndrome, a number of these patients suffer significant infection associated with T-cell immunodeficiency, namely Pneumocystis jiroveci pneumonitis,8 viral pneumonia,9 persistent fungal infection, or viral enteritis, which lead to malabsorption and growth failure. Antiviral and antibacterial prophylaxis may be helpful, but in 1 study group, 18 (41%) of the 44 patients with ICF syndrome died by early adulthood, predominantly as a result of infection or related complications and lymphoid malignancy (C.W., unpublished observation).
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Hematopoietic stem cell transplantation (HSCT) can cure severe combined immunodeficiencies and other immunodeficiencies10,11 by replacing recipient with normal donor hematopoietic stem cells. Although patients with ICF syndrome suffer multisystem disease, death usually results from severe infection or sequelae such as bronchiectasis8; therefore HSCT may be an attractive therapeutic option. Here we report on 3 unrelated patients who underwent HSCT to treat ICF syndrome.
CASE REPORTS
Case 1.
Patient 1 presented with recurrent chest infections after prolonged interstitial pneumonitis in early infancy, which resolved on antibiotic treatment including cotrimoxazole, although P jiroveci was not considered as a diagnosis. She was agammaglobulinemic (Table 1). Cytogenetic studies showed structural aberrations consistent with ICF syndrome; no mutation was identified in DNMT3B, but hypomethylation of 
satellites was demonstrated, which correlates with another subset of patients with ICF syndrome.4 She received immunoglobulin replacement and antimicrobial prophylaxis. She persistently excreted small round structured virus from feces, accompanied by growth failure. At the age of 2.25 years, she underwent HSCT with marrow from a 10/10 HLA-matched unrelated donor after conditioning with alemtuzumab, fludarabine, and melphalan. Cyclosporine was given for graft-versus-host disease (GvHD) prophylaxis. On day 3 she developed severe vomiting and diarrhea with dehydration and acidosis, followed by capillary leak and increasing oxygen requirement. She required ventilation for 3 days and drainage of bilateral pleural effusions. Whole-blood genetic analysis on day 20 showed gain of donor and loss of recipient alleles. She cleared small round structured virus from feces. Cyclosporine was discontinued at 3 months, but the level of donor alleles, measured on whole blood, slipped to 15%. After an unconditioned boost infusion of marrow from the original donor, donor chimerism improved to 100% in all cell lineages and has remained at this level.
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Subsequently, Candida nail and mouth infection resolved with antifungal treatment, and lobar pneumonia resolved with intravenous antibiotics, although no organism was grown. Immunoglobulin was discontinued at 2.5 years after HSCT; she has made normal antibody responses to vaccinations (Table 1). She has had persistent ulceration of the tongue; biopsy of the affected site has not demonstrated GvHD or fungal infection. Her growth has improved, and her weight has risen from 0.4th to the 50th percentile. There has been no evidence of autoimmunity after HSCT.
Case 2.
At 4 months of age, patient 2 had episodic diarrhea and vomiting that settled spontaneously, followed by an upper respiratory tract infection at 6 months. At 7 months of age, she developed pneumonia. She was neutropenic, anemic, and agammaglobulinemic. Cytogenetic analysis demonstrated classic chromosomal anomalies; heterozygous mutations in DNMT3B (Asp809Gly and Val605Ala) confirmed the diagnosis of ICF syndrome. She commenced immunoglobulin replacement and prophylactic cotrimoxazole. At 18 months of age, she underwent HSCT. Routine bronchoalveolar lavage revealed P jiroveci, which was treated with cotrimoxazole. She received marrow from a 10/10 HLA-matched unrelated donor after conditioning with ATG-Fresenius S (Fresenius, Bad Homburg, Germany), busulphan, and cyclophosphamide. Cyclosporine and methotrexate were given for GvHD prophylaxis. Whole-blood genetics on day 27 demonstrated 97% donor alleles. Cyclosporine was discontinued at 6 months and intravenous immunoglobulin at 9 months. At 18 months after HSCT, she made specific immunoglobulin G responses to vaccinations (Table 1).
She has experienced unstable thyroid function since the transplantation with positive antithyroid autoantibodies and biochemical evidence of hypothyroidism and hyperthyroidism. The donor's thyroid status is unknown.
Case 3.
Patient 3 was born at term from consanguineous parents. A previously affected sister had died as a result of infection at 3 years of age. The diagnosis was confirmed postpartum by cytogenetic and DNMT3B mutational analysis, which demonstrated homozygous 2397-11G
A.12 The patient was agammaglobulinemic; immunoglobulin supplementation was started at 2 months. At 2 years he suffered Campylobacter lari infection that resulted in prolonged diarrhea, postinfectious enteropathy, and growth failure. Intestinal symptoms persisted in the absence of infections. At 4 years of age, HSCT was performed from an HLA-identical sister (the donor was homozygous for wild-type DNM3TB) after conditioning with busulphan and cyclophosphamide. GvHD prophylaxis consisted of cyclosporin and methotrexate. Full donor chimerism was demonstrated from day 30 onward. Cyclosporin was discontinued 5 months after HSCT. The diarrhea resolved, and he thrived; his height has risen from less than the 0.4th centile before HSCT to the 2nd to 9th centiles after HSCT, and his weight remains between the 2nd and 9th centiles. He made good responses to vaccination 4 months after HSCT after discontinuation of immunoglobulin replacement (Table 1); pneumococcal vaccination was not given at this point. Vitiligo developed 1 year after HSCT, and Streptococcus pneumoniae meningitis from which he recovered, albeit with the sequelae of serious hearing loss. Eighteen months after HSCT, the donor developed autoimmune hypothyroidism and, subsequently, so did the patient; both of them responded to thyroxine supplementation. At the time of this writing, it has been 2 years after HSCT, and the patient is well.
DISCUSSION
These cases demonstrate that HSCT corrects ICF syndrome–associated immunodeficiency. All the patients were hypogammaglobulinemic and had normal immunoglobulin levels after HSCT, with normal responses to vaccine antigen, including polysaccharide antigen. Furthermore, some B cells demonstrated the memory B-cell phenotype and evidence of class switching, which is not found with ICF syndrome.7
Patients 1 and 3 experienced sustained infection-induced enteritis before HSCT. T-cell immune reconstitution led to resolution of gut symptoms and resumption of normal growth. Patients 2 and 3 experienced autoimmune phenomena, described after HSCT but not described with ICF syndrome. Patient 3 was euthyroid before HSCT; disease was probably donor derived. Nevertheless, vitiligo developed after HSCT. It is not possible to deduce with such a small number of patients whether ICF syndrome is genuinely a risk factor for the development of autoimmunity after HSCT similar to that seen in cases of mixed chimerism after HSCT for Wiskott-Aldrich syndrome.13,14
Although ICF syndrome is not caused by an intrinsic hematopoietic stem cell defect, abnormalities in gene expression critical for B-cell immunoglobulin isotype switching and lymphocyte activation and migration have been observed.15 Agammaglobulinemia is the most obvious immunologic abnormality at presentation, but a number of patients experience complications that are more suggestive of significant T-cell immunodeficiency. Recent studies in murine models seem to support the impact of ICF mutations on T-cell development.16 Critically, donor B-cell reconstitution will be required in ICF syndrome to achieve full immune reconstitution, with B-cell function.
CONCLUSIONS
These 3 patients tolerated either full myeloablative cytoreductive conditioning with busulphan/cyclophosphamide or reduced-intensity conditioning with fludarabine/melphalan, with no significant demonstrable toxicity. HSCT can cure humoral and cellular ICF syndrome–associated immunodeficiency. Given the poor survival without HSCT and these results, HSCT should be considered for patients with ICF syndrome with clinical and/or laboratory evidence of T-lymphocyte dysfunction. Additional studies may ascertain the risk of developing autoimmune-mediated sequelae after HSCT, emphasizing the importance of international databases that record the outcome of patients with these rare syndromes.
FOOTNOTES
Accepted May 2, 2007.
Address correspondence to Andrew R. Gennery, MD, Newcastle General Hospital, Westgate Road, Newcastle Upon Tyne NE4 6BE, United Kingdom. E-mail: a.r.gennery{at}ncl.ac.uk
Drs Gennery and Slatter initiated the study, analyzed the data, and wrote the article; Drs Bredius and Lankester provided patient material and helped write the article; Drs Hagleitner, Weemaes, and Cant provided patient material and helped write the article; and all authors checked the final version of the manuscript.
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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  M M Hagleitner, A Lankester, P Maraschio, M Hulten, J P Fryns, C Schuetz, G Gimelli, E G Davies, A Gennery, B H Belohradsky, et al. Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome) J. Med. Genet., February 1, 2008; 45(2): 93 - 99. [Abstract] [Full Text] [PDF]
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