Unusual complications after bone marrow transplantation for dyskeratosis congenita


Dr Vanderson Rocha Unite de Recherche Clinique — Pavillon Lallier, Hospital Saint Louis, 1 av Claude Vellefaux, Paris, France.


Dyskeratosis congenita (DC) is a rare inherited disorder often associated with aplastic anaemia. We report the cases of five boys transplanted with an HLA-identical related donor for severe aplastic anaemia (SAA) associated to DC; in all cases successful engraftment was observed. Three patients died 2–8 years after bone marrow transplantation (BMT) with signs of endothelial cell damage syndrome (kidney microangiopathy and liver veno-occlusive disease). Another boy died 1 year after BMT from Evans syndrome and invasive aspergillosis. One boy currently presents anaemia, polyarthritis of unknown origin, pulmonary fibrosis and gut malabsorption 7.5 years after BMT. SAA associated with DC can be successfully treated by allogeneic BMT. However, these early and late complications observed are very unusual after BMT and probably reflect the association of transplanted-related factors, evolution of the underlying disease, and increased sensitivity of endothelial cells. Modified conditioning approaches, advances in supportive care and surveillance of these unusual complications offer the possibility of improved outcome for these patients.

Dyskeratosis congenita (DC) is a rare genetic disorder, usually inherited in an X-linked manner, and clinically characterized by three main features: nail dystrophy, reticulate pigmentation and leucoplakia, especially of the mucous membranes. Bone marrow failure occurs in 45–75% of cases ( Drachtman & Alter, 1992). Clinical manifestations often appear during childhood and in rare cases the marrow abnormalities may appear before the skin manifestations. DC has occasionally been confused with Fanconi anaemia (FA), since both syndromes have involvement of skin, an association with bone marrow failure, and a predisposition for malignancy. Chromosomal breakage is increased with diepoxybutane or mitomycin-C in all cases of FA, but only rarely in DC. Studies on DC fibroblasts have shown abnormalities in morphology, growth rate, and numerous unbalanced chromosomal rearrangements in the absence of any clastogens and appear to correlate with the clinical evolution of the disease ( Dokal & Luzzatto, 1994). The median survival following diagnosis of aplastic anaemia associated to DC is approximately 4 years ( Drachtman & Alter, 1992). There is no specific treatment for DC. BMT was performed in approximately 15 patients with a high incidence of both immediate and delayed morbidity and mortality. Mortality was the result of graft-versus-host disease (GVHD), veno-occlusive disease (VOD), liver failure, and idiopathic pulmonary fibrosis ( Langston et al, 1996 ). We have already described two cases of late vascular complications after BMT for DC ( Berthou et al, 1991 ). We report these and other unusual complications observed after BMT in three additional patients.


Five patients with SAA associated with DC underwent allogeneic BMT at the Hôpital St Louis between 1979 and 1993. Pre-transplant patients' characteristics are listed in Table I. Diagnosis of FA was excluded by normal cytogenetics findings. Patients 1 and 2 were the subject of a previous report ( Berthou et al, 1991 ).


Characteristics of the marrow donors, conditioning regimen, number of nucleated cells infused, engraftment, prophylaxis and occurrence of GVHD, and complications observed after BMT are outlined in Table II.

Unusual complications and outcome after BMT

Patient 1

A nephrotic syndrome was diagnosed 6 years after transplant. High levels of plasma endothelial markers were detected: von Willebrand factor antigen at 680% (normal values 50–150%); tissue plasminogen activator (tPA) 34 ng/ml (normal values < 15 ng/ml); fibronectin 480 μg/ml (normal values 110–150 μg/ml). These abnormal endothelial parameters were maintained throughout the patient's illness. After 5 months the patient developed hepatomegaly and ascites without modification of the liver function tests. Clinical treatment was not successful and a surgical porta-cava shunt was performed. Surgical exploration of the abdomen showed ascites, small bowel fibrosis, peritoneal adhesions and portal hypertension. Liver histology showed centrolobular lesions of veno-occlusive disease (VOD) and there was no sign of viral chronic hepatitis. Eight years after BMT the child had transient neurologic dysfunction, fluid retention, jaundice and renal insufficiency, and died in March 1987. An autopsy was performed. In addition to hepatic VOD, histology of the lung showed concentric subintimal thickening and lumen narrowing by fibrosis of terminal lung venules. The kidneys revealed important histological lesions consistent with a thrombotic microangiopathic arterial syndrome (TMAS).

Patient 2

This patient developed a nephritic syndrome 1 year after BMT. The abnormalities were associated with thrombocytopenia (56 × 109/l). Improvement was not observed after stopping cyclosporine A (CsA) and the patient developed hypertensive crisis and renal function deterioration. In April 1985, 2 years and 4 months after BMT, the patient died from cerebral haemorrhage. Post-mortem, kidney histological examination demonstrated severe glomerular and vascular lesions. The vascular lesions were marked by narrowed lumen, swelling of endothelial cells, and thickening of the subendothelial space by a mucoid or hyaline material. Variable degrees of diffuse interstitial fibrosis and oedema, atrophic or dilated tubules were observed.

Patient 3

Diagnosis of DC was performed after BMT ( Table I). The period post-transplant was marked by a limited cutaneous GVHD. Three years after BMT a liver biopsy was performed, due to persistent increased transaminases, and showed alterations compatible with VOD. Elevated levels of von Willebrand factor was detected at 220% (normal values 70–120%). A retrospective analysis for HCV-PCR showed acute hepatitis C 1 month after transplant with resolution 2 months later (negativity of HCV-PCR on many later occasions). Cryoglobulin test was negative. Five years after BMT the patient presented with acute abdominal pain without peristaltism and fever. Surgical findings revealed a thicked wall of the small bowel without macroscopic perforation, abdominal adherences and infected ascites. Haemocultures were positive for Escherichia coli . A diagnosis of spontaneous peritonitis was made. One year later another liver biopsy confirmed the alterations of VOD and chronic hepatitis. The period between 1992 and 1995 was marked by intermittent fever, articular and abdominal pains and complications of hepatic cirrhosis. At age 17 the patient died of liver failure. Autopsy was denied.

Patient 4

On day 45 after BMT the boy presented mental confusion, hypertension, mild renal failure, red cell fragmentation on blood smear. A diagnosis of TMAS was given and CsA discontinuation led to clinical improvement. On October 1990, 2 months after BMT, acute hepatitis was observed. Retrospective HCV-PCR analysis of the serum showed positivity in this period in comparison to previous negative tests. Serology for HCV was always negative with a positive PCR. The period from January 1991 to 1992 was marked mainly by articular pain and mild normocytic normochronic anaemia. In March 1992 a Raynaud phenomena was observed, but the cryoglobulin test was negative. From June 1993 to January 1998 many episodes of polyarthritis were observed. Extensive tests were performed and infectious and collagen causes were excluded. Three years after BMT he complained of dyspnoea, and spirometry revealed a predominant restrictive pattern. Previous pulmonary function studies were normal (October 1995). Bronchoalveolar lavage excluded viral, fungal, bacterial and Pneumocystis carinii infections. Thoracic computed tomography showed increased diameter of both pulmonary arteries without wall thickening and the presence of interstitial pneumonitis, mainly at the periphery. Pulmonary biopsy revealed signs of lymphocytic interstitial infiltrates, fibrosis without consistent findings of bronchiolitis, concentric subintimal thickening and lumen narrowing by fibrosis of the small and medium arteries. Echocardiogram was normal. Due to occasional episodes of diarrhoea and signs of malabsorption, duodenal and colonic biopsies were performed and showed inflammatory infiltrates with predominance of lymphocytes and some epithelial necrotic areas suggesting GVHD. Special stains did not show infectious disease. Signs of vasculitis were not present. Hepatic biopsy showed limited lymphocyte infiltration and skin biopsy did not reveal signs of chronic GVHD. There was elevated level of von Willebrand factor (VWF) antigen at 385% (normal values 70–120%) as well as activity of VWF at 330% (normal values 70–120%) and factor VIII at 206% (normal values 70–120%). Currently the patient suffers from dyspnoea and the latest respiratory studies showed a deterioration of pulmonary parameters with persistent malabsorption and intestinal haemorrhages.

Patient 5

Myeloid engraftment was detected on day 26 with delayed erythroid engraftment due to major ABO incompatibility. The post-transplant period was marked by episodes of chronic GVHD and CMV disease (gastrointestinal tract and retinitis) partially controlled with corticoids and ganciclovir, respectively. One year after BMT the patient presented Hb 4.4 g/dl, WBC 10.8 × 109/l, platelets 44 × 109/l, reticulocytes 110 × 109/l and increased unconjugated bilirubin. The antiglobulin test was positive with presence of antibodies IgG, IgM and complement. The majority of autoantibodies were anti-C. Peripheral blood smear did not detect significant schizocytes. All markers for collagen disease were negative. Mixed autoimmune haemolytic anaemia associated with thrombocytopenia (Evans syndrome) was diagnosed. At this time, a CMV viraemia was positive. Treatment with gancyclovir and corticoids improved the haemolysis. Five months later the boy presented with another episode of Evans syndrome, with presence of mixed autoantibodies Treatment with corticoids, gammaglobulins and plasmaphereses were ineffective. Two months later the patient died of invasive aspergillosis (Aspergillus fumigatus isolated from skin lesion). Autopsy was denied.


Severe aplastic anaemia (SAA) associated with DC can be treated with allogeneic BMT and long-term survival can be achieved using this approach. However, the long-term survival in approximately 12 transplanted patients reported in the literature is poor ( Langston et al, 1996 ). Transient responses to therapy with androgens, prednisone, splenectomy and haemopoietic growth factors have all been reported ( Smith et al, 1979 ; Russo et al, 1990 ; Putterman et al, 1993 ; Alter et al, 1997 ).

We report five patients transplanted with a related donor for SAA associated with DC with very unusual complications. Four of the five patients had vascular lesions and fibrosis involvement of various organs in the period after transplant. The first two patients died 8 and 2 years after transplant of VOD of liver and lungs and TMAS, respectively. Patient 3 was diagnosed as having DC only 3 years after the transplant when all findings were evident ( Table I). In a few cases reported in the literature the aplastic phase appears before the mucocutaneous manifestations, and diagnosis after transplant is difficult since hyperpigmentation, dystrophic nails and oral leucoplakia are also manifestations of chronic GVHD ( Ling et al, 1985 ; Ivker et al, 1993 ). Patient 3 also showed late vascular complications and died of liver VOD. Patient 4 presented with early TMAS, which was reversible after stopping CsA, and late fibrosis of the lung. Since late vascular complications are unusual after BMT, we speculate that these patients are susceptible to early and late endothelial damage syndromes. Another argument for the hypothesis of sensitivity of endothelial cells in DC is a recent report that there is an augmentation of levels of VWF in non-transplanted patients with DC ( Dokal et al, 1995 ). In our series, high levels of VWF were detected in four out of five patients. Changes in endothelial cells (activation, necrosis and apoptosis) after BMT are consequences of multifactorial aspects: conditioning regimen (mainly irradiation), CsA, infectious disease, GVHD, ‘cytokines storm’ ( Eissener et al, 1996 ; Catani et al, 1996 ). Clinical manifestations of the ‘endothelial syndromes’ encompass a number of syndromes which may represent different manifestations of a single disease spectrum. They all share a common pathophysiology, namely vascular endothelial damage, with platelet aggregation, and sometimes with activation of the coagulation system. Distinction between all these syndromes is made largely on the basis of organ involvement ( Pettitt & Clark, 1994 ): for example VOD (liver), thrombotic thrombocytopenic purpura (kidney and brain), haemolytic uraemic syndrome (kidney), pulmonary leak syndrome, and pulmonary haemorrhage.

Another striking complication in patients transplanted with DC is the high frequency of bronchopulmonary manifestations. Interstitial lung disease not associated with transplantation has been described as a late complication of DC ( Verra et al, 1992 ; Imokawa et al, 1994 ; Dokal, 1996). In a series of eight patients transplanted for SAA associated with DC, three patients showed pulmonary fibrosis and died of respiratory complications ( Langston et al, 1996 ). Other cases of pulmonary fibrosis and respiratory failure have been reported as early and late complications of BMT ( Conter et al, 1988 ; Yabe et al, 1997 ). In our series, patient 4 showed an interstitial pneumonitis secondary to pulmonary fibrosis and lymphoid infiltration. Another striking finding is the presence of fibrosis of the small bowel and abdominal adhesions in two of three patients. Fibrosis of the epicardium, lymph nodes and spleen has also been reported even in non-transplanted patients.

Evans syndrome was observed in patient 5. Although the occurrence of immune thrombocytopenia after BMT is well recognized and generally associated with chronic GVHD ( First et al, 1985 ) a few cases of autoimmune neutropenia ( Koeppler & Goldman, 1988) and haemolytic anaemia ( Haas et al, 1986 ) have been described. Evans syndrome was described in four out of 28 children transplanted with a matched unrelated donor receiving an immunosuppressive conditioning regimen (ATG or OKT3) ( Winiarski et al, 1996 ). Of 123 patients transplanted with an unrelated donor none developed Evans syndrome (E. Gluckman, personal communication). Patient 5 presented repeated episodes of CMV infection. CMV infection may predispose to GVHD and consequent endothelial damage due to altered antigen expression on infected endothelial cells, allowing alloantigen recognition by T cells ( Pettit & Clark, 1994). Some reports suggest the presence of abnormalities of both humoral and cell-mediated immunity in DC patients ( Lee et al, 1992 ). Unfortunately we had not studied immunological function before BMT in this patient, but we suggest that Evans syndrome was a result of B-cell dysregulation due to the underlying disease associated with immunosuppressive conditioning, chronic GVHD and CMV disease.

Given the chromosomal instability in fibroblasts and the correlation with age and clinical evolution of the disease ( Dokal & Luzzattto, 1994), one might speculate that irradiation and chemotherapy given prior to BMT, associated with CsA, GVHD and bacterial and viral infections are contributing factors which may accelerate and enhance the expression of DC phenotype, including an increased sensitivity of endothelial cells to these agents and also the impairment of immunological system. These unusual complications are very specific for these group of patients, since they have not been reported in other constitutional aplastic anaemias (e.g. Fanconi anaemia) ( Gluckman et al, 1995 ).

BMT remains the only curative therapy for AA associated with DC. Endothelial damage/activation syndromes and fibrosis (pulmonary and intestinal) are common complications in these patients after transplantation. A complete evaluation of the liver, respiratory tract and endothelial parameters before transplant are very important. Protection of endothelial cells with heparin, or prostaglandin E1 or urseodoxycholic acid may be useful. Modified conditioning approaches, probably avoiding radiotherapy, advances in supportive care and surveillance of these unusual complications will probably offer the possibility of improved outcome for these patients. Other treatment strategies need to be developed and gene therapy may be a suitable approach, since the gene for the X-linked form has recently been identified ( Heiss et al, 1998 ).