Hyper-IgM syndrome due to CD40 deficiency (HIGM3) is a rare disease with only a few reported cases of haematopoietic stem cell transplantation (HSCT). In retrospective study, we reviewed all patients with HIGM3 who underwent HSCT at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, between 2008 and 2013. Six patients were identified. Three male and three female patients from three families. The median age of diagnosis was 13 months (range, 1–28 months). All lacked CD40 expression on B cells by flow cytometry. The median time from diagnosis to transplantation was 8.5 months (range, 1–17 months). For all patients, the donors were HLA-identical siblings, with the exception of one patient for whom the donor was a sibling with one antigen mismatch. The conditioning regimen was busulfan and cyclophosphamide in five patients and busulfan, cyclophosphamide and antithymocyte globulin in one patient. For GVHD prophylaxis, cyclosporine and methotrexate was used. All patients engrafted. The survival rate was 100%, with a median follow-up of 54 months (range, 30–116 months). One patient developed acute GVHD. All patients showed complete immune recovery with positive CD40 expression on B cells and discontinued IVIG replacement. Our study shows that HSCT is potentially effective at curing the disease.
Hyper-IgM syndrome due to CD40 deficiency (HIGM3) is a rare form of primary immunodeficiency. Affected patients have a genetic deficit in the immunoglobulin isotype class-switch recombination (CSR) and somatic hypermutation (SHM) pathways. This genetic deficit can result from a mutated cell surface molecule, such as an autosomal recessive lack of CD40 on the surfaces of B cells and antigen-presenting cells . Patients present in infancy with recurrent bacterial, viral and opportunistic infections, as well as protracted diarrhoea, failure to thrive and severe neutropenia . HIGM3 patients have a high rate of morbidity and mortality. Previously, we reported a series of patients in which third had Pneumocystis jiroveci pneumonia (PJP), and half of the patients had chronic diarrhoea due to Cryptosporidium and devastating sclerosing cholangitis . Haematopoietic stem cell transplantation (HSCT) has been shown to be a curative option, however, few reported cases of successful HSCT have been published in the medical literature, and no cohort of patients has ever been reported [4,5,6]. This lack of published experience in HSCT for HIGM3 syndrome is a result of the extreme rarity of the disease; for example, only one and seven patients are registered in the United States Immunodeficiency Network (USIDNET)  and the European Society for Immunodeficiencies (ESID) registry , respectively. Few case reports and case series describing the clinical phenotype have been published [3, 5, 9,10,11,12]. In this study, we report for the first time a single-centre experience of HSCT in a cohort of six patients with HIGM3 syndrome.
Materials and methods
This is a retrospective study for six patients with HIGM3 who received HSCT at King Faisal Specialist Hospital and Research Centre (KFSH and RC) in Riyadh, Saudi Arabia, between 2008 and 2013. The six patients belonged to three families (three patients from family 1, two patients from family 2 and one patient from family 3) (1a, 1b, 1c, 2a, 2b and 3). Two patients’ (1a and 2a) HSCT outcomes were previously reported . All the patients resulted from consanguineous marriages. All six patients’ diagnoses were confirmed by demonstrating the absence of CD40 expression on B cells as previously described by O’Gorman et al. . Data were acquired on a FACS-Calibur flow cytometer (Becton Dickinson, San Jose, CA, USA) and analyzed using Cell Quest software. The mutation in the CD40 gene of the three patients from family 1 was a missense homozygous mutation for 170 C > T, and the other three patients (2a, 2b and 3) a splice site homozygous mutation for c. 256 + 2 T > C. The mutation analysis was described and characterized in a previous publication . The median age of diagnosis was 13 months (range, 1–28 months). Patient 2b was diagnosed by screening at the age of 1 month because of family history and had no significant manifestations of the disease at the time of HSCT. In contrast, the other patients showed significant disease manifestations (Table 1).
Five patients suffered from recurrent chest infection (patients 1a, 1b, 1c, 2a and 3), two of them had complicated bronchiectasis (1a and 1b). Failure to thrive was a prominent feature in most of the patients. Two patients had cryptosporidium and sclerosing cholangitis (1a and 1b), and three patients had protracted diarrhoea (patients 1a, 1b and 3). Four patients had neutropenia (patients 1a, 1b, 2a and 3); two of them also had perianal ulcers. One patient had cytomegalovirus (CMV) viremia before transplantation that was treated with IV ganciclovir (1b). One patient had severe oral and oesophageal candidiasis complicated by recurrent oesophageal stenosis and oesophageal-pulmonary fistula (1a). No patient presented with PJP or BCGitis. All six patients started intravenous immune globulin (IVIG) and PJP prophylaxis prior to HSCT.
Conditioning regimen and GVHD prophylaxis
The pre-transplant conditioning regimen for all six patients included the intravenous administration of busulfan at a dose of 1 mg/kg/dose Q6h for 4 days, from transplant day –10 to day –7 (total dose 16 mg/kg) and intravenous cyclophosphamide at 50 mg/kg on days –5 to –2 (total dose 200 mg/kg). One patient (2b) also received ATG at 10 mg/kg. All patients received graft-versus-host disease (GVHD) prophylaxis that consisted of cyclosporine (CsA) and 3 doses of methotrexate (MTX) at standard doses (Table 2). In the absence of GVHD, CsA was tapered after 100 days. For all five patients, the grafts were non-manipulated bone marrow from HLA full matched siblings expect for one patient (2b) where the donor was a sibling with a single antigen mismatch (Table 2).
All patients were isolated in high efficiency particulate air -filtered or laminar flow facilities during the transplantation. All blood products were irradiated and leukocyte filtered. All patients received acyclovir prophylaxis at a dose of 500 mg/m2/dose intravenous every 8 h for 28 days starting –3 pre-bone marrow transplant if the donor was CMV positive. Engraftment was defined as an absolute Neutrophil Count > 0.5 × 109/L and a platelet count of > 20,000 × 106/L for 3 consecutive days. Chimerism was analyzed using short tandem repeat polymorphisms. CD40 expression was assessed through flow cytometry.
Statistical analyses were performed using descriptive statistics for continuous variables, which was reported as the median, and categorical variables were summarized as frequencies and percentages.
Six patients with HIGM3 syndrome underwent HSCT at a median age of 19 months (range, 6–44 months). The patients were treated at a median of 5.5 months post-diagnosis (range, 1–17 months). The median dose of CD34-positive cells was 8.2 106/kg per kg of recipient body weight. The median time to neutrophil recovery was 15 days (range, 12–20 days). The median time to platelet engraftment was 31 days (range, 16–44 days) (Table 2). One patient developed drug-induced nephrotoxicity (1b), and another patient (2b) developed grade 2 acute skin GVHD (day + 27 post-HSCT) and responded to 1 mg/kg/day of systemic steroids for 7 days. This patient (2b) also had veno-occlusive disease (VOD), which was resolved with the use of diuretics, and haemorrhagic cystitis secondary to cyclophosphamide, which was resolved with hyperhydration. Within the first year post-HSCT, all six patients’ discontinued IVIG replacement and started vaccination according to protocol. The median post-transplant chimerism rates for donor percentage of lymphocytes and myeloid cells in the last follow-up were 66.6% (range, 16–100%) and 75.5% (range, 51–100%), respectively. Four patients showed a positive specific vaccination response, whereas in two patients the test was not done (Table 2). The overall survival and cure rates were 100% at a median follow-up of 54 months (range, 30–116 months).
HIGM3 is a rare form of autosomal recessive combined immunodeficiency caused by mutations in the CD40 gene . The standard of care for patients has been providing prophylactic IVIG replacement, antibiotics and granulocyte-colony stimulating factor for episodes of neutropenia, as well as close follow-up and management of infections and hepatobiliary-related complications. Nevertheless, patients are still at high risk for morbidity and mortality. We previously reported on a cohort of 11 patients with HIGM3 and showed that opportunistic infections, sclerosing cholangitis and mortality occurred in 72, 45 and 27% of these patients, respectively . In studies of a similar but more common form of HIGM syndrome due to CD40 L deficiency (HIGM1), opportunistic infections with PJP was reported in 41% of the patients , sclerosing cholangitis due to cryptosporidium in one report was found in 19.6% of patients and mortality occurred in 23% of the patients . Therefore, patients with defects in CD40 or CD40 L have a poor long-term prognosis despite full supportive treatment, and HSCT has becomes a viable option for curing this disease, especially if the patient has a full-match donor. However, a recent report by de la Morena et al. showed that there was no statistically significant difference in overall survival between XHIGM patients treated with HSCT and those who were not (P = 0.67), although median Lansky/Karnofsky scores were significantly higher in those surviving following HSCT (P < 0.001) . However, the incidence of sclerosing cholangitis due to cryptosporidium in this cohort of mostly North American and European patients was low compared with the incidence in other populations, such as the Saudi population  (20 vs. 45%).
To date, only three reports of four patients with HIGM3 who underwent HSCT are available in the medical literature. The first case was reported in 2003 and is for a child with disseminated cryptosporidium infection and sclerosing cholangitis who underwent non-myeloablative conditioning from a fully matched brother donor; unfortunately this patient died from severe pneumonia on day 16 post-transplant with no evidence of engraftment. The second case is of a successful stem cell transplantation reported by Mazzolari et al.  for a 3-year-old female. She received haematopoietic stem cells from her matched sibling and underwent a myeloablative conditioning regimen . Then, in 2012, our group reported two patients (1a and 2a) who are included in the present cohort. To the best of our knowledge, this is the largest cohort of HIGM3 patients who have undergone transplantation at a single centre. The present study shows a successful outcome with survival rate of 100% and complete cure for all patients. We used myeloablative conditioning for all patients (busulfan and cyclophosphamide), and although two patients had cryptosporidium infection and sclerosing cholangitis (1a and 1b) before HSCT, none of them developed VOD or liver GVHD following the HSCT. Both patients had complete recovery of liver function. In conclusion, HSCT with myeloablative conditioning in the early stage of the disease and an HLA-matched sibling donor is potentially effective at curing the disease with fewer complications. Other donor types such as a matched unrelated donor, haploidentical donor or umbilical cord blood has not been reported for HIGM3 thus far.
Ferrari S, Giliani S, Insalaco A, Al-Ghonaium A, Soresina A, Loubser M, et al. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper-IgM. Proc Natl Acad Sci USA. 2001;98:12614–19.
Lougaris V, Badolato R, Ferrari S, Plebani A. Hyper immunoglobulin M syndrome due to CD 40 deficiency: clinical, molecular, and immunological features. Immunol Rev. 2005;203:48–66.
Al-Saud BK, Al-Sum Z, Alassiri H, Al-Ghonaium A, Al-Muhsen S, Al-Dhekri H, Arnaout R, et al. Clinical, immunological, and molecular characterization of hyper-IgM syndrome due to CD40 deficiency in eleven patients. J Clin Immunol. 2013;33:1325–35.
Kutukculer N, Aksoylar S, Kansoy S, Cetingul N, Notarangelo LD. Outcome of hematopoietic stem cell transplantation in hyper-IgM syndrome caused by CD40 deficiency. J Pediatr. 2003;143:141–42.
Mazzolari E, Lanzi G, Forino C, Lanfranchi A, Aksu G, Ozturk C, et al. First successful stem cell transplantation in a child with CD40 deficiency. Bone Marrow Transplant. 2007;40:279–81.
Al-Dhekri H, Al-Zum Z, Al-Saud B, Ayas M, Al-Muhsen S, Arnaout R, et al. Successful outcome in two patients with CD40 deficiency treated with allogeneic HCST. Clin Immunol. 2012;143:96–8.
Leven EA, Maffucci P, Ochs HD, Scholl PR, Buckley RH, Fuleihan RL, et al. Hyper IgM syndrome: a report from the USIDNET registry. J Clin Immunol. 2016;36:490–501.
Gathmann B, Grimbacher B, Beauté J, Dudoit Y, Mahlaoui N, Fischer A, et al. The European internet-based patient and research database for primary immunodeficiencies: results 2006–8. Clin Exp Immunol. 2009;157(Suppl 1):3–11.
Fontana S, Moratto D, Mangal S, De Francesco M, Vermi W, Ferrari S, et al. Functional defects of dendritic cells in patients with CD40 deficiency. Blood. 2003;102:4099–106.
Kutukculer N, Moratto D, Aydinok Y, Lougaris V, Aksoylar S, Plebani A, et al. Disseminated cryptosporidium infection in an infant with hyper-IgM syndrome caused by CD40 deficiency. J Pediatr. 2003;142:194–6.
Karaca N, Forveille M, Aksu G, Durandy G, Kutukculer N. Hyper-immunoglobulin M syndrome type 3 with normal CD40 cell surface expression. Scand J Immunol. 2012;76:21–5.
Mishra A, Italia K, Gupta M, Desai M, Madkaikar M. Hyperimmunoglobulin syndrome due to CD40 deficiency: possibly the first case from India. J Postgrad Med. 2015;61:46–8.
O’Gorman MR, Zaas D, Paniagua M, Corrochano V, Scholl PR, Pachman LM. Development of a rapid whole blood flow cytometry procedure for the diagnosis of X-linked hyper-IgM syndrome. Clin Immunol Immunopathol. 1997;85:172–81.
Qamar N, Fuleihan RL. The hyper IgM syndromes. Clin Rev Allergy Immunol. 2014;46:120–30.
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.
de la Morena MT, Leonard D, Torgerson TR, Cabral-Marques O, Slatter M, Aghamohammadi A, et al. Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation. J Allergy Clin Immunol. 2017;139:1282–92.
Conflict of interest
The authors declare that they have no conflict of interest.
About this article
Cite this article
Al-Saud, B., Al-Jomaie, M., Al-Ghonaium, A. et al. Haematopoietic stem cell transplant for hyper-IgM syndrome due to CD40 defects: a single-centre experience. Bone Marrow Transplant 54, 63–67 (2019). https://doi.org/10.1038/s41409-018-0219-0
Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Diseases: Current Status and Future Perspectives
Frontiers in Pediatrics (2019)
Reactions Weekly (2019)