Omenn syndrome is a rare subtype of severe combined immunodeficiency. Affected patients present recurrent infections, lymphadenopathy, skin eruptions, eosinophilia, hepatosplenomegaly, failure to thrive, and gastrointestinal complications with variable severity. A 3-month-old female infant, born to consanguineous healthy parents, presented with splenomegaly, erythroderma, failure to thrive, and history of recurrent otitis media, hypothyroidism, and Bacille Calmette-Guérin lymphadenitis following Bacille Calmette-Guérin vaccination. The immunologic workup showed lymphopenia; low levels of CD3+ T cells, CD4+ T cells, and CD8+ T cells; normal levels of CD19+ B cells and CD16+/CD56+ natural killer cells; hypogammaglobulinemia; and a high level of serum immunoglobulin E. She was clinically diagnosed with T-B+NK+ severe combined immunodeficiency. Genetic study revealed a missense homozygous alteration (c.617G>A, p.Arg206Gln) in exon 5 of the IL7R gene in the patient, as well as carrier states for the same variant in both parents. The patient received a peripheral blood stem cell transplant from a matched unrelated donor. A reduced intensity conditioning regimen was applied, including fludarabine, melphalan, rabbit antithymocyte globulin, and graft-versus-host disease prophylaxis by cyclosporine and mycophenolate mofetil. She clinically improved, and after engraftment the donor chimerism was 100% at 1 year after transplant. Hematopoietic stem cell transplant is a curative therapeutic option for patients with Omenn syndrome and, when combined with an early diagnosis, can prevent complications and improve patient survival.
Key words : Hematopoietic stem cell transplantation, Interleukin 7 receptor alpha chain, Pediatric transplant, Recombinase activating gene
Omenn syndrome, a rare subtype of severe combined immunodeficiency (SCID), is characterized by early-onset generalized protein-losing erythroderma, hepatosplenomegaly, polyadenopathy, failure to thrive, and recurrent infections, with normal to high nonfunctional T cells and either hypereosinophilia or elevated serum immunoglobulin E (IgE).1
Omenn syndrome is mostly inherited in an autosomal recessive manner and therefore is more common in consanguineous marriages. Omenn syndrome is mostly caused by missense alterations in the recombinase activating genes (RAG-1 and RAG-2), leading to the disruption of V(D)J recombination and generation of oligoclonal T lymphocytes. However, alterations in other genes including ARTEMIS, ADA, ILRA2, ILRA7, CHD7, RMRP, and DNA ligase 4 and the 22q11 micro-deletion syndrome may be the underlying defect in Omenn syndrome.2
To date, hematopoietic stem cell transplant (HSCT), enzyme replacement therapy, and gene therapy are proposed for SCID and related disorders.3 However, HSCT has only a moderate prognosis in Omenn syndrome due to complications by highly activated Omenn T cells, resulting in delayed T-cell engraftment and a high rate of graft failure.4
Because timely management of this condition is lifesaving, in this case report, we aim to share our experience with a successful transplant in a female infant with Omenn syndrome.
A female infant, 3 months of age and the first child of consanguineous (third degree) parents, was referred to the Mofid Children’s Hospital with splenomegaly and generalized exfoliative skin rash (erythroderma). She also had an umbilical hernia, recurrent otitis media, and failure to thrive. She had received complete vaccinations and developed localized Bacille Calmette-Guérin (BCG) lymphadenitis following BCG vaccine inoculation.
An overview of laboratory investigations at the reference date is summarized in Table 1. She had lymphopenia and normocytic anemia. Bone marrow analysis showed mildly hypercellular marrow with a left shift in myeloid series. Malignancy and hemophagocytic lymphohistiocytosis were ruled out. The HIV antibody test was negative. The immunologic workup revealed normal levels of CD19+ B cells and CD16+/CD56+ natural killer cells; low levels of CD3+, CD4+, and CD8+ T cells; hypogammag-lobulinemia; and high serum IgE. The T-cell human leukocyte antigen (HLA)-DR expression was 31%. The number of T-cell receptor excision circles (ie, TREC) copies was undetectable, whereas kappa-receptor excision circles (ie, KREC) copies were normal. She was clinically diagnosed with T-B+NK+ SCID. She underwent skin biopsy, which revealed parakeratosis, marked spongiosis, patchy intraepidermal lymphocytic infiltration, focal vacuolar degeneration of basal layer with pigment incontinence, and a few necrotic keratinocytes, all of which are consistent with Omenn syndrome. The diagnosis was confirmed by genome analysis of a sample of whole blood through the whole-exome sequencing method, which revealed a missense alteration (c.617G>A, p.Arg206Gln) in exon 5 of the IL7R gene (NM_002185.5). This variant is assigned “uncertain significance” in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/), and both parents were heterozygous for the same variant. Informed written consent for the publication of this report was provided by the patient’s parents. The reporting of this study conforms to CARE case report guidelines.5
Treatment due to her axillary BCG lymphadenitis was performed, including rifampin, isoniazid, ethambutol, and clarithromycin, along with supplemental vitamin B6. She also received prophylaxis of fluconazole and trimethoprim/sulfa-methoxazole.
During the pretransplant period, she experienced episodes of fever and skin rashes but was in a stable clinical condition with supportive care. The patient received intravenous immunoglobulin every month. She required blood transfusions several times. The patient’s hypothyroidism was diagnosed at 5 months before transplant, for which levothyroxine treatment was started.
Based on the diagnosis of SCID disease (Omenn syndrome) in the absence of a matched sibling donor or a matched related donor, the patient received HSCT at 14 months of age from a fully matched unrelated donor. The cytomegalovirus (CMV) IgG test of the recipient was negative, but the donor CMV IgG test was positive. The blood group of the recipient was B positive, and the donor’s blood group was O positive. The source of transplant was peripheral blood stem cells with 8 × 108 cells/kg total nucleated cell count and 7 × 106 CD34 cells/kg and 175 × 106 CD3 cells/kg.
A reduced intensity conditioning (RIC) regimen was used, which included fludarabine (30 mg/m2/d for 5 days), melphalan (70 mg/m2/d for 2 days), and rabbit antithymocyte globulin (Thymoglobulin, Sanofi-Aventis; 2.5 mg/kg/d for 3 days). Cyclosporine (3 mg/kg/d divided into 2 daily intravenous doses on day -1) and mycophenolate mofetil (CellCept, 15 mg/kg twice daily, orally, on day +1) were applied for graft-versus-host disease (GVHD) prophylaxis. The antimicrobial prophylaxis protocol included voriconazole, acyclovir, and cotrimoxazole for the underlying immunodeficiency. After transplant, ciprofloxacin was added to the regimen.
Also, from the first days of admission, she received topical corticosteroids to treat severe skin rash, erythema, scaling, and edema. Granulocyte colony-stimulating factor (5 μg/kg/d intravenous) was started on day +3. She was engrafted on day +12. First chimerism on post-HSCT day +15 was 95% and reached 100% on her follow-up at 1 year after HSCT.
The complications included gastrointestinal GVHD stage 3 (on day +16) and skin GVHD stage 3 (on day +34), which were treated with methylprednisolone, sirolimus, and supportive care.
Presently, 1 year after allogenic HSCT, the patient remains clinically stable and maintains a follow-up schedule in the HSCT and immunology clinics. The immunosuppressive therapy has been discontinued. The latest chimerism was 100%, and all compli-cations have improved. She receives levothyroxine for hypothyroidism. She maintains follow-up in the infectious clinic for the BCG lymphadenitis and receives isoniazid. She also receives monthly treatments of intravenous immunoglobulin therapy with regular checks of the serum IgG level.
Herein, we discussed a successful HSCT with peripheral blood stem cell source and RIC regimen in a patient with Omenn syndrome that led to remarkable clinical improvement and 100% donor chimerism.
The history of Omenn syndrome refers back to 1965, when Omenn published a description of a typical Omenn syndrome in an Irish American family characterized by recurrent infections, skin eruptions, eosinophilia, with accompanied respiratory, gastroin-testinal symptoms, and failure to thrive.6 With Omenn syndrome, the number of T lymphocytes may be normal or high, and eosinophils are slightly increased.7 Hypomorphic RAG alterations were identified as the leading cause of Omenn syndrome in 1998,8 affecting V(D)J recombination, which is responsible for gene assembly of T cell receptor and immunoglobulins and for the differentiation of B cells and T cells. Therefore, the absence of T lymphocytes and B lymphocytes is the accepted result of gene targeting of RAG-1 and RAG-2 in mice, whereas natural killer cells were not affected. In humans, partial RAG function leads to Omenn syndrome, whereas completely inactivated RAG gene causes the T-B- SCID phenotype.9
According to the previous studies, HSCT could be a prominent curative approach for inborn alterations of immunity due to the dependence of the immune system on myeloid cells. Our patient’s diagnosis age was 3 months, and the transplant was done at 14 months. Age at HSCT is an important factor that may affect the successful outcome. Some studies have shown that early HSCT in newborns can lead to greater thymic output and increased rates of survival in SCID patients; however, other studies have indicated that the clinical state at the time of HSCT is more effective than age to predict successful outcomes of HSCT in patients with Omenn syndrome.10 The index patient tested negative for CMV at the time of transplant; however, the donor had a positive CMV test result. It is known that CMV infection can cause serious problems and death in SCID patients, because infection control after HSCT is limited by antiviral drug toxicities and/or the occurrence of probable drug-resistant strains.11 Success rates for HSCT are higher in patients who receive transplant before infection occurrence and early in life (3.5 months of age or younger); donor status and/or conditioning methods are also important factors.12 All cases of Omenn syndrome have led to fatal outcomes within 2 months from birth unless stem cell transplant is performed in these patients. Moreover, these patients are usually diagnosed late, which leads to increased risk of mortality due to untreated ensuing complications.13 According to these observations, newborn screening is needed to facilitate the best possible outcome.
The RIC regimen that we applied included fludarabine, melphalan, and rabbit antithymocyte globulin. Elimination of autoreactive T lymphocytes in HSCT by aggressive conditioning regimens is correlated with high treatment-related mortality, especially in patients with prior organ damage due to severe/recurrent infection; on the other hand, RIC is less toxic than myeloablative conditioning agents, and thus we observe an increasing trend in the application of RIC regimen as an alternative. The use of RIC prevents graft rejection and maintains stable donor-derived hematopoiesis that is sufficient for HSCT. In Omenn syndrome, the mortality rate is higher than in other SCID variants, which may be directly or indirectly attributed to peritransplant autoimmunity complications. The complications of our case include gastrointestinal and skin GVHD grade 3. Graft failure and rejection, infection, GVHD (acute and chronic), and death have been reported as HSCT outcomes for patients with Omenn syndrome. Rituximab (anti-CD20 monoclonal antibody) injection has been reported to have a very good response (>80%) for refractory post-HSCT autoim-mune hemolytic anemia. Furthermore, use of ruxolitinib for controlling graft-versus-host-like disease (ie, GVHLD) was found to be effective based on a randomized phase 3 trial on patients with steroid-refractory disease. However, cytopenia has been reported as a frequent adverse event associated with the use of ruxolitinib, as well as increased susceptibility to infections; thus, infection prevention care is mandatory.14 In 2005, Mazzolari and colleagues retrospectively studied the outcome of HSCT in 11 unselected patients with Omenn syndrome between 1991 and 2002. The mean age of the patients at the time of the first HSCT was 8.4 months. Two patients received 2 HSCT procedures, and 1 patient received 3 HSCT procedures. The resulting 15 HSCT were derived in 7 cases from HLA-haploidentical parents, in 4 patients from matched unrelated donors, in 3 cases from an HLA phenotypically identical related donor, and in 1 case from an HLA genotypically identical family donor. At the time of the most recent evaluation, all the 9 survivors had a normal T-cell function, and 8 of them had developed normal antibody production. That study demonstrated an overall mortality of 18.2%.15
Pourvali and colleagues reported a patient with atypical Omenn syndrome due to a RAG2 gene alteration who received allo-HSCT at the age of 11 months from a matched sibling donor using a minimal dose of busulfan as a conditioning regimen; however, he died 2 months later due to severe infection.16
Because finding a matched donor is a limitation of HSCT, gene therapy has been introduced in various RAG-deficient models. Nevertheless, tight regulation and expression of RAG within the cell cycle can constrain the clinical application of gene therapy.17
Although SCID can be successfully treated by allogenic HSCT, which provides a long-term life span, it is also an interesting object for gene therapy based on recent observations. Through studies on patients who are deficient for adenosine deaminase, clinicians found the condition of one group to be better than expected; after follow-up investigations on this group, they found out that revertant alterations led to partial correction of the SCID phenotype. As a result, we theorize that a small group of lymphocytes with revertant alterations is expected to auto-amplify and constitute a larger group. Therefore, we should consider gene therapy as an alternative treatment with probable fewer toxic effects. Hematopoietic stem cell transplant is a curative therapeutic option for patients with Omenn syndrome and can remarkably improve clinical features and survival and reduce the mortality rate; however, more studies are needed to prove these findings and reveal the best therapeutic option. Also, genetic analysis of the immediate family members of the affected individual should be concurrently performed to discover whether a sibling(s) may also be at risk for developing this disease, so that preventive measures could be taken to avoid the condition once and for all.
Volume : 21
Issue : 2
Pages : 189 - 193
DOI : 10.6002/ect.2022.0348
From the 1Pediatric Congenital Hematologic Disorders Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran; the 2Student Research Committee, Alborz University of Medical Sciences, Karaj; the 3Immunology and Allergy Department, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran; and the 4Pediatric Nephrology Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Acknowledgements: We thank the patient and the patient’s family for their contribution to this study. Data for this study were taken from the disease registry titled “Data registry of Hematopoietic Stem Cell Transplantation in pediatrics group (0-18 years) in Shahid Beheshti University of Medical Sciences and allied centers” (code No. IR.SBMU.RICH.REC.1399.026), in accordance with the ethical committee, which was supported by the Deputy of Research and Technology at Shahid Beheshti University of Medical Sciences (http://dregistry.sbmu.ac.ir). Other than described, the authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Amirreza Paksaz, Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran; or Mahnaz Jamee, Pediatric Nephrology Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Table 1. Laboratory Investigations at 3 Months of Age
Figure 1. Generalized Erythroderma Before Transplant