Peripheral blood immunophenotyping in a large cohort of patients with Shwachman–Diamond syndrome

Shwachman–Diamond syndrome (SDS) is one of the more common inherited bone marrow failure syndromes, characterized by neutropenia, occasional thrombocytopenia, and anemia. Bone marrow evaluation reveals an increased number of monocytes and mature B cells along with decreased granulocytes. However, little is known about the subpopulations of peripheral blood cells, and few previous publications have been based on a small number of patients. Here, we report a comprehensive immunophenotypic analysis from a cohort of 37 SDS patients who display impairment mostly in the myeloid compartment with a deficiency also in the number of B cells and CD4/CD8 double‐negative T cells.     

Shwachman–Diamond syndrome: Nationwide survey and systematic review in Japan

Background

Shwachman–Diamond syndrome (SDS) is a rare multisystem disorder associated with exocrine pancreatic insufficiency. The present study reports the results of a nationwide survey and a systematic review on SDS to develop consensus guidelines for intractable diarrhea including SDS.

Methods

Questionnaires were sent to 616 departments of pediatrics or of pediatric surgery in Japan in a nationwide survey. A second questionnaire was sent to doctors who had treated SDS patients and included questions on clinical information. Additionally, a systematic review was performed using digital literature databases to assess the influence of medical (i.e. non‐surgical) treatment on SDS prognosis.

Results

Answers were received from 529 institutions (85.9%), which included information on 24 patients with SDS (median age, 10.4 years; male, n = 15) treated from January 2005 to December 2014. Although 75% of patients received pancreatic enzyme replacement therapy, there was no significant association between treatment and prognosis. Systematic review identified one clinical practice guideline, two case series, eight case reports and 26 reviews. Patient information from those studies was insufficient for meta‐analysis.

Conclusions

The rarity of SDS makes it difficult to establish evidence‐based treatment for SDS. According to the limited information from patients and published reports, medical treatment for malabsorption due to SDS should be performed to improve fat absorption and stool condition, but it is not clear whether this treatment improves the prognosis of malabsorption.     

Breast cancer in a case of Shwachman Diamond syndrome

Shwachman Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome (IBMFS) characterized by neutropenia, exocrine pancreatic dysfunction, and cancer predisposition. Patients are at risk for myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) but, unlike other IBMFS, there have been no reported cases of solid tumors. We report a novel case of a solid tumor in a patient with SDS and biallelic mutations in the Shwachman Bodian Diamond Syndrome gene (SBDS). Whether the development of breast cancer in this patient is due to SDS or an isolated case due to unknown factors requires further study. Pediatr Blood Cancer 2012; 59: 945–946. © 2011 Wiley Periodicals, Inc.     

A family with Hoyeraal–Hreidarsson syndrome and four variants in two genes of the telomerase core complex

We describe an African American family with Hoyeraal–Hreidarrson syndrome (HHS) in which 2 TERT mutations (causing P530L and A880T amino acid changes) and two in the DKC1 variants (G486R and A487A) were segregating. Both genes are associated with dyskeratosis congenita and HHS. It was important to determine the importance of these mutations in disease pathogenesis to counsel family members. From genetic analysis of family members, telomere length and X‐inactivation studies we concluded that compound heterozygosity for the TERT mutations was the major cause of HHS and the DKC1 G486R variant is a rare African variant unlikely to cause disease. Pediatr Blood Cancer 2013; 60: E4–E6. © 2013 Wiley Periodicals, Inc.     

Safety of hematopoietic cell infusion in children with malignant and non‐malignant diseases

HPC infusions have been associated with a variety of adverse events related to either patient or HPC product‐related factors. Studies documenting infusion‐related AEs in children are limited. We reviewed HPC infusion records in 354 children. Infusion‐related adverse events were classified as follows: grade 0—absent, grade I—mild, grade II—moderate, grade III—severe, grade IV—life‐threatening, and grade V—death. The percentage of patients with grade 0, I, and II‐IV AEs was as follows: 0 = 67%, I = 23.4%, and II‐V = 9.6% (one patient had fatal anaphylactic reaction to dimethyl sulfoxide). The incidence of grade II‐IV hypertension was 7.1%. There was a higher incidence of AEs with infusion of allogeneic bone marrow versus allogeneic PBSCs (47.4% vs 25.3%, P = .001). Cryopreserved products had a lower incidence of infusion‐associated AEs compared with fresh HPC products (24% vs 39.4%, P = .003). Allogeneic HPC infusion volume (>100 mL) was a significant risk factor for infusion‐associated AEs (P < .001). Patients >10 years who received autologous HPC infusions had higher risk of AEs when compared to patients <10 years (P = .01). Our study demonstrated that despite a high incidence of infusion‐associated hypertension, HPC infusion is relatively safe in children. Investigating strategies to optimize management of hypertension in the setting of HPC infusion is warranted.     

Effects of cytokines on hematopoietic progenitor cells in cord blood,in bone marrow,and in peripheral blood mobilized by chemotherapy and G-CSF

We compared the effects of various combinations of cytokines (stem cell factor [SCF], interleukin [IL] ?3, IL-6, granulocyte-colony stimulating factor [G-CSF], erythropoietin [EPO]) among the growth of human hematopoietic progenitor cells from cord blood (CB), bone marrow (BM), and peripheral blood mononuclear cells (MNC) mobilized by chemotherapy and G-CSF (PB) in a semi-solid medium. Macroscopic colonies, that were visible to the naked eye, were formed from PB-MNC within 1 week even without cytokines. They consisted of blasts containing macrophage-like cells with immature nuclei on Wright stain, and were strongly accelerated by IL-3. Macroscopic colonies were also formed from CB-MNC. However, they appeared after 1–3 weeks and synergistic effects of SCF with other cytokines, especially EPO, were prominent. Macroscopic colonies were not formed from BM-MNC. Granulocyte-colony stimulating factor was effective in increasing colony forming units of granulocyte macrophage from BM-MNC and they appeared between 1 and 2 weeks. These results suggested that the quality of hematopoietic progenitor cells was different among blood sources. This might lead to different bone marrow recovery patterns after transplantation of each blood source. The appropriate cytokines should be added to evaluate their exact potential.     

Early diagnosis of Maroteaux-Lamy syndrome in two patients with accelerated growth and advanced bone maturation

The diagnosis of mucopolysaccharidosis (MPS) VI is usually not made before the age of 2 or 3 years when the main clinical signs of dwarfed stature, skeletal deformities, coarsening facies, stiff joints and hepatosplenomegaly described in textbooks are recognisable. Conversely, accelerated growth with advanced bone age, a precocious feature of this condition although not suggestive of a storage disorder, is usually neither recognised, nor adequately interpreted. We report on two infants with MPS VI who presented with these two unexpected features within the 1st year of life. Conclusion:recognition of precocious excessive growth in a mucopolysaccharidosis enables an early diagnosis, the prime responsibility of the clinician, in order to propose early treatment like bone marrow transplantation or active recombinant sulphatase therapy, and appropriate genetic counselling.Abbreviation MPS mucopolysaccharidosis     

The incidence of autoimmune hemolytic anemia in pediatric hematopoietic stem cell recipients post‐first and post‐second hematopoietic stem cell transplant

The reported incidence of post‐allogeneic HSCT AIHA was between 4.4% and 6% following a single transplant. Cord blood transplantation, T‐cell depletion, and chronic GvHD are significantly associated with post‐transplant AIHA. During an 11‐yr period, data for 500 pediatric HSCT recipients were eligible for evaluation of the incidence of AIHA post‐first and post‐second transplants. Demographic, transplant, and post‐transplant‐related variables were analyzed. Twelve of 500 (2.4%) recipients at a median of 273 days and seven of 72 (9.7%) recipients at a median of 157 days developed AIHA post‐first and post‐second HSCT, respectively. Post‐first HSCT, none of the MRD recipients developed AIHA (0/175 MRD vs. 12/325 other donors, p = 0.04). Four of 12 required a second HSCT to control the AIHA. After the second HSCT, MUD was significantly associated with the development of AIHA. No other variables were associated with the post‐second transplant AIHA. The incidence of AIHA post‐first and post‐second HSCT was less than the reported. The increased incidence of AIHA among recipients of second HSCT is most likely due to the profound immune dysregulation. A much larger, prospective study would be needed to evaluate the incidence, complications, and management of post‐transplant AIHA.     

A novel SAMD9 variant identified in patient with MIRAGE syndrome: Further defining syndromic phenotype and review of previous cases

We present here a case of MIRAGE syndrome due to novel variant (c.2318T>C) in the sterile α motif domain‐containing protein 9 (SAMD9) gene. Previous reports have described the clinical phenotype, which includes myelodysplasia, recurrent infections, restriction of growth and development, adrenal insufficiency, genitourinary abnormalities, and enteropathies, often resulting in fatality within the first few years of life. This report illustrates the variability in phenotype by describing an 11‐year‐old male, diagnosed with MIRAGE at age 9 years when his novel variant was identified through whole exome sequencing. A brief review of previously published cases of MIRAGE syndrome and the genotypic and phenotypic spectrum are presented.     

Successful use of reduced‐intensity conditioning and matched‐unrelated hematopoietic stem cell transplant in a child with Diamond‐Blackfan anemia and cirrhosis

For patients with DBA who are transfusion dependent, HSCT is the only cure. Chronic transfusions can lead to cirrhosis secondary to iron overload, making them poor candidates for myeloablative HSCT. RIC regimens are associated with lower morbidity and mortality compared to myeloablative regimens, but use of RIC in DBA has been limited. Here we present a 14‐yr‐old girl with DBA and multiple comorbidities including liver cirrhosis, who underwent MUD HSCT utilizing a RIC regimen that is novel to this condition. She tolerated the regimen well, and at 21 months, she remains transfusion independent with chimerisms at 99%.     

中国儿童Shwachman-Diamond综合征的表现特征与诊治研究

为阐明中国儿童Shwachman-Diamond综合征（SDS）的疾病特征，作为临床早期诊断和合理治疗的参考依据，该文通过网络收集历年文献报道的27例中国SDS患儿的临床资料，分析归纳中国儿童SDS流行病学、临床特征和诊治要点，并与国际文献病例资料进行对比。结果显示，中国儿童SDS男女之比约2：1，起病年龄 < 1个月至5岁（中位数1个月），确诊年龄3个月至12岁（中位数12个月）。27例SDS患儿均存在骨髓造血抑制所致外周血细胞减少，其中中性粒细胞缺乏最常见（93%）。慢性腹泻（85%）、肝脏损害（78%）和身材矮小（83%）是SDS的三大临床特征。补充胰酶和成分输血等可能暂时缓解病情，异基因造血干细胞移植仍为有效根治措施。与国外资料对比显示，中国SDS患儿慢性腹泻、外周3系血细胞减少和肝脏损害的发生率均高于欧美，突变基因类型也存在一定差异。     

Chimerism of allogeneic mesenchymal cells in bone marrow,liver, and spleen after mesenchymal stem cells infusion

Although an infusion of culture‐expanded MSCs is applied in clinic to improve results of HSCs transplantation and for a treatment of musculoskeletal disorders, homing, and engraftment potential of culture‐expanded MSC in humans is still obscure. We report two female patients who received allogeneic BM transplantation as a treatment of hematological diseases and a transplantation of MSCs from third‐party male donors. Both patients died within one yr of infectious complications. Specimens of paraffin‐embedded blocks of tissues from transplanted patients were taken. The aim of the study was to estimate possible homing and engraftment of allogeneic BM‐derived MSCs in some tissues/organs of recipient. Sensitive real‐time quantitative PCR analysis was applied with SRY gene as a target. MSC chimerism was found in BM, liver, and spleen of both patients. We conclude that sensitive RQ‐PCR analysis is acceptable for low‐level chimerism evaluation even in paraffin‐embedded tissue specimens.     

Successful treatment of non‐Hodgkin's lymphoma using R‐CHOP in a patient with Wiskott–Aldrich syndrome followed by a reduced‐intensity stem cell transplant

WAS is an X‐linked primary immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and increased incidence of autoimmunity and malignancy. HSCT is the only curative treatment for WAS. Herein, we report the case of a 17‐yr‐old boy with WAS who received an unrelated HSCT while in complete remission of diffuse large B‐cell lymphoma after chemotherapy. Pretransplant conditioning consisted of fludarabine, busulfan, and total body irradiation (4 Gy). GvHD prophylaxis consisted of tacrolimus and short‐course methotrexate. Following HSCT, rapid and stable engraftment was observed. Platelet count gradually increased, and the generalized eczema improved. The patient developed grade II acute GvHD and limited chronic GvHD on days 30 and 210, respectively, which resolved with immunosuppressive treatment. Symptoms caused by the reactivation of human herpes virus‐6, BK virus, and VZV were observed from days 21, 60, and 96, respectively; they were resolved after conservative treatment and acyclovir administration. No other regimen‐related toxicity was observed. Complete donor bone marrow chimerism was achieved one month after transplantation. RIST is an effective therapeutic option for older children with WAS accompanied by malignant lymphoma.