Bone marrow transplantation in Shwachman–Diamond syndrome: report of two cases and review of the literature

Abstract

Summary:Patients with Shwachman-Diamond syndrome (SDS) have an increased frequency of myelodysplasia and leukemic transformation. We described two patients who received allogeneic stem cell transplantation and developed multiple complications, including seizure, hyperglycemia and renal tubular acidosis. A review of the literature showed that patients with SDS appeared to have an increased incidence of various transplantassociated problems. These patients frequently have underlying organ dysfunction and should be managed with extreme caution when treated with allogeneic stem cell transplantation. Keywords: Shwachman-Diamond syndrome; myelodysplasia; leukemia; BMT; complications Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by exocrine insufficiency, short stature, skeletal abnormalities and bone marrow dysfunction. There is an increased risk of marrow aplasia and leukemic transformation, the latter often preceded by a phase of myelodysplasia (MDS). 1,2 Allogeneic stem cell transplantation offers potentially curative treatment for MDS, leukemia and marrow failure syndromes. Few patients with SDS have undergone BMT. We report our experience of allogeneic BMT in two SDS patients who developed MDS and monosomy 7 abnormality. Severe complications were encountered in both cases. We reviewed the outcome of allotransplantation in other patients published in the literature and noticed a significant number of post-transplant problems. Case 1An 8-year-old boy with MDS/monosomy 7 had a past history of short stature, growth hormone deficiency, recurrent diarrhea and loss of mineralization of distal femora. CT scan of the abdomen showed a fatty pancreas and serum amylase and lipase activity were virtually absent. He received a CD5, CD8 T cell-depleted (Applied Immune Sciences, Santa Clara, CA, USA), unrelated donor (micromismatched at 1 HLA-DR locus) BMT after conditioning with thiotepa 5 mg/kg i.v. on day −7, CY 60 mg/kg i.v. on day −6, −5 and TBI 3 Gy/day on days −4 to −1. GVHD prophylaxis included CsA, short Mtx and MP. The post-BMT course was complicated by several episodes of seizure of unknown etiology. Later on he developed severe electrolyte wasting as the result of renal tubular acidosis. He had grade IV GVHD that failed to respond to MP, antithymocyte globulin and hydroxychloroquine therapy. He became severely hyperglycemic (blood sugar Ͼ1000 mg%) and hypernatremic after pulse MP therapy. This responded slowly to insulin and hydration. He died on day 93 of pulmonary hemorrhage. An autopsy was not performed. His ANC exceeded 500/mm 3 on day 18 but he remained platelet and red cell transfusion-dependent. A bone marrow examination on day 31 showed 1.2% blasts and normal cytogenetics. Case 2A 9-year-old child with a history of short stature, growth hormone deficiency, and metaphyseal chondroplasia developed marrow hypoplasia. Bone marrow examination 2 years later revealed myelofibrosis, with monosomy 7 and + i(7q) cytogenetic abnormalities. A MRI of the abdomen showed hemosiderosis...

Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman–Diamond syndrome

“…Tsai et al 15 reported a case of fatal congestive heart failure following a Cy-containing-conditioning regimen. Other authors have described neurological complications, 16 pulmonary complications and multiorgan failure with typical ablative regimens. 17,18 In this report, we describe our institutional experience with the use of a reduced-intensity-conditioning regimen consisting of Campath-1H, fludarabine and melphalan in seven patients with SDS, all of whom achieved excellent hematopoietic recovery and full donor chimerism with acceptable toxicity.…”

Bone marrow transplantation in Shwachman–Diamond syndrome

“…There also does not appear to be a significant increase in transplant-related morbidity and mortality in SDS patients compared to other transplant populations, in contrast to previous observations. 7 Patients who received an allotransplant for marrow aplasia had a considerably better survival compared to patients transplanted for other reasons. Four of the five patients with marrow aplasia were disease free for at least 9 months after transplant in contrast to other indications where only two patients survived beyond a year.…”

“…Early attempts were associated with significant toxicity and mortality which were thought to be related to nonspecific organ dysfunction caused by the syndrome. 7 We report a patient with SDS who received an allotransplant without significant 100 day transplant-related toxicity. We also reviewed the outcomes of other patients published in the literature and noticed several trends that may provide some guidance in the timing of allotransplants in patients with SDS.…”

Successful unrelated bone marrow transplantation for Shwachman–Diamond syndrome

“…Including this report, only 11 cases of allogeneic transplant have been reported in the literature. 3,4,[9][10][11][12][13][14] Indications for transplantation were marrow aplasia (five cases), myelodysplastic syndrome (three cases) and acute myeloid leukemia (three cases). Only five of 11 were alive at follow up, and four of them were disease-free survivors with follow-ups ranging from 9 months to 5 years.…”

“…2 Supportive treatment with antibiotics and transfusion, and correction of malabsorption with oral pancreatic enzymes, currently allow prolonged survival without modifying the natural evolution of the disease. 1,2 Allogeneic stem cell transplantation is a valuable option when clonal disorders such as leukemic transformation, myelodysplasia or severe marrow aplasia develop 3,4 but experience in this field is very limited due to the rarity of the disease and the lack of clear-cut indications concerning the optimum timing of transplantation. We report a successful unrelated identical bone marrow transplant (BMT) in a 5-year-old boy who developed marrow aplasia after initial marrow dysplasia.…”