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Shwachman-Diamond syndrome is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities, and short stature. We describe the clinical characteristics, laboratory data, and treatment in a 14-month-old boy diagnosed with this syndrome in our unit.
The clinical phenotype of Shwachman-Diamond syndrome (SDS) is extremely heterogeneous, showing a wide range of abnormalities and symptoms. The main characteristics of the syndrome are exocrine pancreatic dysfunction, haematologic abnormality and growth retardation. At diagnosis, especially when made in infancy, symptoms of pancreatic insufficiency are always present. This condition could be considered as a transient pancreatic insufficiency. In fact, several studies have shown that, with advancing age, about 40-60% of patients become pancreatic sufficient. Observations on the evolution of pancreatic activity lead us to believe that the diagnosis of SDS must be considered even in the absence of signs and symptoms of pancreatic insufficiency. Intermittent neutropenia is the most common haematological finding in SDS, but more of the bone marrow cellular elements can be involved. In recent years, recombinant human granulocyte colony-stimulating factor has been used in some SDS subjects with severe neutropenia and frequent infection. The major haematological problem in the disease is the appearance of acute myeloid leukaemia; however, its prevalence is difficult to establish. Growth retardation is a typical manifestation. Weight and length are deficient at birth and remain below normal over time. Some studies show that SDS patients present short stature rather than malnutrition and this would suggest an inherent growth problem. A broad spectrum of skeletal abnormalities has been found to be associated with this syndrome. Short ribs with broadened anterior ends and metaphyseal dyschondroplasia of the long bone are the most common findings. Elevated liver enzymes and hepatomegaly are present in the first years of life with subsequent improvement without complications. Developmental delay, learning disorders and attention deficit disorders are also reported.
Shwachman-Diamond syndrome (SDS) is characterized by exocrine pancreatic insufficiency, skeletal abnormalities and hematological dysfunction. The genetic analysis of the SBDS gene and the long-term follow-up of a 37-year-old man with SDS, osteoporosis and type 1 diabetes are reported. Analysis of the SBDS gene revealed a compound heterozygous genotype with 7 mutations. This genotype is the result of the inheritance of abnormal alleles from both healthy parents. We identified putatively non-functional gene conversions from the SBDS pseudogene into the otherwise normal SBDS gene in each of the parentally inherited alleles. The association of SDS and type 1 diabetes mellitus seems to be coincidental and not associated to distinct mutations of the SBDS gene. Osteoporosis in patients with SDS may be the result of a primary defect of the bone metabolism and not of a nutritional problem, although our patient had chronic hypophosphatemia. The long-term follow-up of this patient provides interesting insights into the course of SDS, showing the complexity of genotype-phenotype correlations and the possible influence of other modifying genes and/or environmental factors that might determine the phenotypic presentation of SDS in an individual patient.
The effect of lithium treatment on the impaired neutrophil chemotactic function of a patient affected by Shwachman-Diamond syndrome is reported. We found that (1) a cytoskeletal cellular defect seems to be involved in the impairment of neutrophil function (and perhaps of cellular secretion and chondrocyte function) in the syndrome; (2) intermittent neutropenia is always present in the syndrome, and (3) lithium seems capable, in addition to its capacity of inducing leukocytosis, of modulating leukocyte functions by modulating the microtubular system. The drug, at usual therapeutic dosage, was able to normalize neutrophil functions without side effects. As no therapy is available in this syndrome to date, our data suggest the therapeutic use of lithium in order to improve these cytoskeleton-mediated functions and the degree of neutropenia.
The case of a patient suffering from Gardner-Diamond syndrome is described. Owing to the uncertain etiology, we suggest that the functional platelet defect found may intervene, maintaining and making the ecchymotic lesions worse.
Three new ophthalmological instruments are described: a rotating contact glass holder for easier control of the three-mirror Goldmann or other diagnostic contact lens which must be rotated on the eye; a suture-tying forceps combined with a sapphire blade, combining the tying and cutting functions in one instrument and a diamond cystotome for anterior capsulectomy with a cutting edge of unequalled sharpness.
BACKGROUND: In patients with left ventricular dysfunction, atrial fibrillation and flutter (AF and AFl, respectively) are common arrhythmias associated with increased morbidity and mortality. The present study investigated the potential of dofetilide in AF-AFl patients with left ventricular dysfunction to restore and maintain sinus rhythm, which might reduce mortality and hospitalizations. METHODS AND RESULTS: In the Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies, 506 patients were in AF-AFl at baseline. Over the course of study, cardioversion occurred in 148 (59%) dofetilide- and 86 (34%) placebo-treated patients. In these patients, the probability of maintaining sinus rhythm for 1 year was 79% with dofetilide versus 42% with placebo (P<0.001). Dofetilide had no effect on all-cause mortality, but restoration and maintenance of sinus rhythm was associated with significant reduction in mortality (risk ratio [RR], 0.44; 95% CI, 0.30 to 0.64; P<0.0001). In addition, dofetilide therapy was associated with a significantly lower risk ratio versus placebo for either all-cause (RR, 0.70; 95% CI, 0.56 to 0.89; P</=0.005) or congestive heart failure (RR, 0.69; 95% CI, 0.51 to 0.93; P</=0.02) rehospitalization. CONCLUSIONS: Dofetilide is safe and increases the probability of obtaining and maintaining sinus rhythm in patients with structural heart disease. The present study suggests that restoration of sinus rhythm is associated with improved survival.
Five diamond polishers with interstitial lung disease attributed to cobalt not alloyed to carbides of hard metals are described. The exposure originated from high-speed grinding tools with a polishing surface of microdiamonds cemented in very fine cobalt. Mineralogic analysis of lung tissue, lavage fluid, filtered air, and exhaust dust in the work environment revealed cobalt as the only toxic agent. Complaints consisted of work-related rhinitis, cough, chest tightness, dyspnea, anorexia, and weight loss, and were intensified in the absence of an adequate exhaust ventilation. Three subjects were in a rather subacute stage, as documented by open lung biopsy in 2 of them, and had a severe restrictive defect and markedly decreased diffusing capacity. Two patients presented a more chronic histologic pattern and had a less decreased diffusing capacity. Open lung biopsies showed in these 4 a fibrosing alveolitis, mainly of the centrilobular zones. In the former 2 patients, subacute lesions consisting of a mural mononuclear cell infiltrate, marked intra-alveolar desquamation, and multinucleated giant cells were found, whereas in the latter 2, centrilobular fibrosis with some microcyst formation was also already seen. Multiple multinucleated giant cells were present in the bronchoalveolar lavage fluid. Interruption of the exposure, with or without corticotherapy, caused a rapid regression of the complaints and a partial improvement of lung function.
To explore the etiology of congenital hypoplastic anemia (CHA) or the Diamond-Blackfan anemia, erythropoietin responsive committed erythroid precursors were enumerated by the plasma clot method. These included blood and marrow erythroid burst-forming units (BFU-E) and marrow erythroid colony-forming units (CFU-E). The peripheral blood nucleated cells of 11 patients and the marrow cells of seven of these patients were examined. Studies were repeated in several patients during relapse and after induction of remission. BFU-E were undetectable in the marrow and blood of all but one relapsed patient, and the numbers of marrow CFU-E were depressed in all relapsed patients. Blood BFU-E remained low in all of the patients in remission. No evidence was obtained for suppression of normal CFU-E or BFU-E by CHA lymphocytes. Erythropoietin dose-response curves performed in two patients revealed a 10-fold increase in erythropoietin requirement for marrow CFU-E colony growth. This marked unresponsiveness to erythropoietin was strikingly improved by steroid therapy in one patient. We suggest that CHA is the result of a qualitative and/or quantitative deficiency of BFU-E. If BFU-E are produced, they must be relatively unresponsive to erythropoietin. The abnormal BFU-E give rise to erythropoietin unresponsive CFU-E and, thence, to proerythroblasts that are, in turn, trapped in that early stage of development because of their poor erythropoietic response. Hence, red cell production is deficient. Steroids appear to improve the erythropoietin response of CHA erythroid precursors.
Clinically inapparent persistent chronic liver disease in a 15-month-old male patient with Shwachman-Diamond syndrome is presented. Cryptic hepatic involvement may be an unrecognized feature of the syndrome and should be evaluated in all cases.
A number of different culture media have been described for use in the diagnosis of Tritrichomonas foetus infection in bulls, and recently, a commercial culture kit has become available. The objective of this study was to compare the sensitivity of 2 culture-based diagnostic tests for T. foetus in bulls. One test used a commercial kit for transport and culture of the samples. The other test used a thioglycollate transport medium (TFTM) for transport and a modified Diamond's medium (MDM) for culture of the samples. Twenty-one bulls infected with T. foetus were sampled repeatedly. On each sampling day, samples collected from the left and right sides of the bull were tested with one of the 2 diagnostic tests being compared. The effect of the type of diagnostic test on the outcome of the test was evaluated with a chi-square test for the calculated odds ratio. Because repeated tests from the same bull cannot be considered independent measures, unadjusted chi-square tests were adjusted for the effect of clustering by bull. Samples tested using the commercial kit were 6.95 times as likely to be positive as samples tested with a diagnostic test using MDM (P < 0.001).
Shwachman-Diamond Syndrome (SDS) is a rare multisystem disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, and metaphyseal chondrodysplasia. Recent studies show that mutations of SBDS, a gene of unknown function, are present in the majority of patients with SDS. In the present study, we show that most, but not all, patients classified based on rigorous clinical criteria as having SDS had compound heterozygous mutations of SBDS. Full-length SBDS protein was not detected in leukocytes of SDS patients with the most common SBDS mutations, consistent with a loss-of-function mechanism. In contrast, SBDS protein was expressed at normal levels in SDS patients without SBDS mutations. These data confirm the absence of SBDS mutations in this subgroup of patients and suggest that SDS is a genetically heterogeneous disorder. The presence (or absence) of SBDS mutations may define subgroups of patients with SDS who share distinct clinical features or natural history.
Shwachman-Diamond syndrome (SDS) is an autosomal-recessive disorder characterized by short stature, exocrine pancreatic insufficiency, and hematologic defects. The causative SBDS gene was sequenced in 20 of 23 unrelated patients with clinical SDS. Mutations in the SBDS gene were found in 75%, being identical in 11 patients. Hematologic parameters for all 3 lineages were determined over time such as absolute neutrophil counts (ANCs), granulocyte functions, and erythroid and myeloid colony formation (erythroid burst-forming unit [BFU-E] and granulocyte-monocyte colony-forming unit [CFU-GM]) from hematopoietic progenitor cells, percentage of fetal hemoglobin (HbF), and platelet counts. Persistent neutropenia was present in 43% in the absence of apoptosis and unrelated to chemotaxis defects (in 65%) or infection rate. Irrespective of the ANC in vivo, abnormal CFU-GM was observed in all patients with SDS tested (14 of 14), whereas BFU-E was less often affected (9 of 14). Cytogenetic aberrations occurred in 5 of 19 patients in the absence of myelodysplasia. One child died during allogeneic bone marrow transplantation. In conclusion, neutropenia and defective chemotaxis did not result in severe clinical infection in SDS. CFU-GMs were impaired in all patients tested. From the SBDS sequence data, we conclude that in patients with genetically proven SDS a genotype-phenotype relationship in SDS does not exist in clinical and hematologic terms.
Shwachman-Diamond syndrome (SDS) is an inherited bone marrow disorder with varying cytopenias and a strong predilection to myelodysplastic syndrome (MDS) and acute myeloid leukemia. Previously, it was found that the percentage of CD34(+) cells in bone marrow and the in vitro colony formation from CD34(+) cells of patients with SDS were markedly reduced. For these reasons, and because apoptosis is central in the pathogenesis of bone marrow dysfunction in MDS, this study was initiated to delineate the role of apoptosis in the pathogenesis of the marrow failure. Eleven children with SDS were studied. Compared to normal controls, patients' marrow mononuclear cells plated in clonogenic cultures showed a significantly higher tendency to undergo apoptosis. The defect in SDS was found in patients with and without MDS. Patients showed a more prominent decrease in colony formation and increased apoptosis after preincubation with activating anti-Fas antibody. Fas expression on marrow cells from patients was significantly higher than from normal controls. The difference between patients and controls for Fas expression was also significant for the following cell fraction subpopulations: CD34(-)/CD38(-), CD34(-)/CD38(+), and CD34(+). In conclusion, SDS hematopoietic progenitors are intrinsically flawed and have faulty proliferative properties and increased apoptosis. Bone marrow failure in SDS appears mediated by increased apoptosis as the central pathogenetic mechanism. This increased propensity for apoptosis is linked to increased expression of the Fas antigen and to hyperactivation of the Fas signaling pathway.
Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia that usually presents early in infancy and is inherited in 10% to 20% of cases. Linkage analysis has shown that DBA in many of both dominant and recessive DBA families mapped to chromosome 19q13.2 leading to the cloning of a gene on chromosome 19q13.2 that encodes a ribosomal protein, RPS19. However, subsequently, mutations of the RPS19 gene have only been identified in 25% of all patients with DBA. This study analyzed 14 multiplex DBA families, 9 of which had 19q13.2 haplotypes inconsistent with 19q linkage. A genome-wide search for linked loci suggested the presence of a second DBA locus in a 26.4-centimorgan (cM) interval on human chromosome 8p. Subsequently, 24 additional DBA families were ascertained and all 38 families were analyzed with additional polymorphic markers on chromosome 8p. In total, 18 of 38 families were consistent with linkage to chromosome 8p with a maximal LOD score with heterogeneity of 3.55 at D8S277 assuming 90% penetrance. The results indicate the existence of a second DBA gene in the 26.4-cM telomeric region of human chromosome 8p23.3-p22, most likely within an 8.1-cM interval flanked by D8S518 and D8S1825. Seven families were inconsistent with linkage to 8p or 19q and did not reveal mutations in the RPS19 gene, suggesting further genetic heterogeneity. (Blood. 2001;97:2145-2150)
We studied the in vitro proliferative characteristics of marrow erythroid progenitors, colony forming unit-erythroid (CFU-E) and burst forming unit-erythroid (BFU-E), in two infants with Diamond-Blackfan syndrome before and during prednisone treatment. Patient 1, had a brisk erythropoietic response to prednisone and the anemia improved; Patient 2 was steroid-unresponsive. Marrow from Patient 1 yielded linear increases in numbers of colonies in erythropoietin dose-response studies, and the magnitude of response was much greater while on prednisone compared to pretreatment. Cultures of stem cell rich fractions of marrow from Patient 1 separated by unit gravity sedimentation (STA-PUT) revealed moderately reduced CFU-E and BFU-E numbers before prednisone, but normal colony numbers during treatment. Patient 2 differed because CFU-E and BFU-E were almost absent at all erythropoietin doses before and during therapy. Even stem cell rich marrow fraction initially yielded very low colony numbers which did not increase significantly while on prednisone. These findings suggest that in Patient 1 there were adequate numbers of progenitors that were able to differentiate normally only in the presence of prednisone. In Patient 2 the erythropoietic failure in vivo and in vitro was unaffected by prednisone.
To study the action of corticosteroids on erythroid precursors, (burst forming unit-erythroid and colony forming unit-erythroid) in Diamond-Blackfan Syndrome (DBS), marrow from a newly diagnosed untreated infant was studied in vitro with prednisone and dexamethasone. This patient subsequently proved to be steroid responsive. Colony numbers increased linearly in an erythropoietin (EPO) dose response study. There was marked enhancement of colony numbers at all EPO doses after adding either prednisone (10(-6) M) or dexamethasone (10(-9) M) to the cultures. The data indicate that corticosteroids augment erythropoiesis at both early (BFU-E) and late (CFU-E) stages of development in DBS. In contrast, marrow from a second infant with DBS, clinically steroid resistant, failed to respond to steroids in vitro.
The two main goals of this study were: to determine how O2 uptake, ventilation, and CO2 production during exercise were acutely affected by transfusion in children with congenital anemia (thalassemia major and Diamond-Blackfan syndrome) requiring hypertransfusion and chelation therapy and to compare gas exchange responses to exercise of the anemic patients to normal values. Thirteen patients (age range 7-27) performed cycle ergometry with a progressively increasing work rate. Gas exchange was measured breath-by-breath. Tests were done before and after routine transfusion (mean increase in hematocrit 22%). The results were compared to 10 age-matched normal children who performed the same protocol on two occasions separated by a 2-day interval, and to the results of 109 normal children studied in this laboratory. Transfusion resulted in: a small, but significant increase in the anaerobic threshold (9%) and an increase in the slope of the relationship between O2-uptake and heart rates. Despite these improvements, the majority of the patients had abnormally low values of maximal O2 uptake, anaerobic threshold, and slope of the O2 uptake-heart rate relationship. The abnormalities were more marked in the older patients. Measurement of gas exchange during exercise may be helpful in determining an optimal hematocrit for patients on hypertransfusion regimens.