Down syndrome and esophageal cancer

We present two cases of Down syndrome with inoperable esophageal cancer at a relatively young age. The first patient had a locally advanced squamous cell carcinoma of the distal esophagus. The second had a short circular adenocarcinoma of the distal esophagus with peritoneal and liver metastases. The cases are discussed with regard to the current literature on Down syndrome and esophageal cancer.     

Down syndrome and acute lymphoblastic leukaemia

Acute lymphoblastic leukaemia in children with Down syndrome (ALL-DS) is characterised by unique clinical and biological features. Notable among these are an absence of ALL in DS patients <1 year of age; a lower incidence of favourable and unfavourable chromosomal translocations; heightened sensitivity to methotrexate; and an increased propensity to infections. Although children with ALL-DS have historically fared less well than their non-DS counterparts (ALL-NDS), recent data indicate that outcomes in ALL-DS are now comparable with ALL-NDS with risk-adapted therapies, after adjusting for biological differences between the ALL-DS and ALL-NDS populations. Given the increased risk of ALL-DS patients for treatment-related toxicities, further intensification of therapy may not yield continued improvements in survival. Future investigations in the ALL-DS population should focus on maintaining excellent outcomes while reducing treatment-related complications through novel treatment strategies, such as the integration of targeted noncytotoxic agents.     

Evaluation of coeliac disease serological markers in Down syndrome patients

BACKGROUND: The increased incidence of coeliac disease in patients with Down syndrome makes screening of coeliac disease in this population advisable. AIM: Evaluation of efficiency of different serological markers to detect coeliac disease in Down syndrome patients. PATIENTS: A total of 56 Down syndrome patients (aged: 1-17 years) were included in study. METHODS: Patients were evaluated for both IgG and IgA anti-transglutaminase antibodies and for anti-gliadin IgA and IgG antibodies using either purified omega-gliadin, wheat ethanol extract or commercial gliadin. Patients who had at least one positive result were evaluated for antiendomysium antibodies using either monkey oesophagus or human umbilical cord by indirect immunofluorescence. Coeliac disease was diagnosed by typical histological changes on duodenal mucosa. RESULTS: Increased levels of at least one anti-gliadin IgA and IgG antibody marker were found in 27 out of 56 cases (26 for IgG and 9 for IgA). 11/56 were positive for IgG anti-transglutaminase antibodies and two of them were also positive for IgA anti-transglutaminase antibodies and anti-endomysium antibodies. These two patients were finally diagnosed as coeliacs. Gliadin antigenic fractions employed produced differences in the performance of the anti-gliadin IgA and IgG antibody test. The use of commercial gliadin or wheat ethanol extract showed low sensitivity in IgA anti-gliadin IgA and IgG antibody determination, whereas good sensitivity and specificity were observed with omega-gliadins. IgG anti-transglutaminase antibodies showed a high proportion of false positive results (9 out of 56), whereas anti-endomysium antibodies and IgA anti-transglutaminase antibodies presented an excellent correlation with presence of active coeliac disease. CONCLUSIONS: Two out of 56 Down syndrome patients were diagnosed as coeliacs, corresponding to an incidence of 3.6%. The use of omega-gliadin presented the best efficiency in anti-gliadin IgA and IgG antibody determination whereas IgA anti-transglutaminase antibodies and anti-endomysium antibody determination showed an absolute correlation with presence of active coeliac disease.     

Cancer predisposition syndromes associated with myeloid malignancy

The majority of myeloid malignancies are caused by sporadic somatic events rather than cancer predisposition. Nonetheless, the identification of hereditary cancer predisposition syndromes is critical when caring for patients with myeloid malignancies since detection may direct decisions related to cancer treatment and surveillance. A positive genetic test result also has important implications for other family members who can use this information to undergo their own testing to determine their cancer risk. We review the demographics, genetic mechanisms of disease, diagnostic approach, malignancy risk, and management for the following five cancer predisposition syndromes associated with myeloid malignancies: Li-Fraumeni, constitutional mismatch repair deficiency, Werner, Bloom, and Nijmegen breakage.     

Distinctive hematological abnormalities in East Asian neonates and children with Down syndrome

Introduction: Neonates with Down syndrome (DS) are predisposed to developing transient abnormal myelopoiesis (TAM) and acute myeloid leukemia (AML) associated with DS. However, there is a paucity of data on hematological aberrations and GATA1 mutations in neonates with DS in East Asian populations. Methods: Total 109 patients with DS who had one or more CBCs obtained were enrolled. The molecular analysis of the GATA1 gene performed in 10 patients (three TAM, three AML associated with DS at diagnosis, one remission case of AML associated with DS and three DS without TAM or AML). Results: East Asian DS neonates showed low frequency of thrombocytopenia, uncommon neutrophilia and higher prevalence rate of TAM compared to previous reports from western countries. GATA1 mutations were identified in almost all TAM and AML associated with DS samples, but were not detected in the samples from DS without TAM or AML associated with DS. Conclusion: East Asian DS neonates and children showed distinctive spectrum of hematological abnormalities.     

Outcome of Down syndrome associated acute lymphoblastic leukaemia treated on a contemporary protocol

We report the outcome for children and young people with Down syndrome‐associated acute lymphoblastic leukaemia (DS‐ALL) treated on a contemporary protocol. Compared with non‐DS ALL, patients with DS‐ALL had an inferior event‐free survival (65·6% vs. 87·7% at 5 years; P < 0·00005) and overall survival (70·0% vs. 92·2%; P < 0·00005). Excess treatment‐related mortality – was primarily responsible for the worse outcomes for DS‐ALL (21·6% at 5 years, vs. 3·3%, P < 0·00005). Minimal residual disease (MRD) risk status was highly discriminant for relapse in DS patients with 0/28 relapses in the MRD low risk group.     

Airway anomalies in children with Down syndrome: endoscopic findings

Down syndrome (DS) is the most common chromosomal anomaly in humans. Numerous congenital malformations associated with DS have been described. However, there are insufficient data available about airway anomalies. Our objective was to characterize the clinical presentation, frequency, and type of airway anomalies in a population of patients with DS. A retrospective evaluation of flexible bronchoscopies performed in 24 DS patients due to significant respiratory morbidity was compared to the findings in 324 non-DS patients during the same time period. The procedure was carried out under sedation, using an Olympus BF3C20 bronchoscope. The main indications for the procedure were atelectasis of the right upper lobe (12/24) and stridor (7/24). The most common associated conditions were congenital heart disease (12/24) and reactive airways disease (12/24). The most important endoscopic findings were: laryngomalacia (12/24), tracheomalacia (8/24), tracheal bronchus (5/24), and bronchomalacia (5/24). Only six patients had a normal examination. Multiple airway anomalies (>/=2) were a common finding in this series. We conclude that patients with DS and respiratory symptoms have a high incidence of airway anomalies compared to non-DS patients. The clinician should have a high index of suspicion for airway anomalies in DS patients with respiratory symptoms.     

Outcomes of patients with Down syndrome and acute leukemia: A retrospective observational study

Children with Down syndrome (DS) have a higher risk of developing acute leukemia than do those without DS. There are few studies in the literature about outcome, survival, and difficulties of treating patients with DS and acute leukemia in a developing country. This study aimed to analyze the outcome, response to treatment, survival, treatment complications, and causes of death in patients with DS and acute leukemia compared with those in patients with acute leukemia without DS diagnosed in the same period of time.We conducted a retrospective observational analysis including a cohort of 21 patients with DS and acute leukemia diagnosed between 2009 and 2018 in 3 hemato-oncology centers (2 pediatric centers and 1 adult hematology center). A group of patients with DS-acute lymphoblastic leukemia (DS-ALL) was analyzed and compared with a group of 165 patients with acute lymphoblastic leukemia without DS, and a group of patients with DS-acute myeloid leukemia (DS-AML) was analyzed and compared with a group of 50 patients with acute myeloid leukemia without DS, which was diagnosed during the same period of time (2009–2018) and treated under similar conditions in terms of both treatment protocols and economic resources.The overall survival rates in children with DS-ALL and DS-AML were 35.7% and 57.1%, respectively (P = .438). The overall survival rate was significantly worse in children with DS-ALL than in those with acute lymphoblastic leukemia without DS (35.71% vs 75.80%, P = .001). We noted that treatment-related mortality in the patients with DS-ALL was high (50%) (infections and toxicities related to chemotherapy); this result was significantly different from that for patients with leukemia without DS (P < .0001). The relapse rate was higher in patients with DS-ALL but not significantly higher than that in patients without DS (P = .13).In contrast, the overall survival rate was better for patients with DS-AML than for those with acute myeloid leukemia without DS (57.1% vs 45.1%, P = .47).Because of the particularities of the host, we suggest that DS-ALL and DS-AML should be considered as independent diseases and treated according to specific protocols with therapy optimization per the minimal residual disease.     

Transient myeloproliferative disorder in neonates without Down syndrome: case report and review

Transient myeloproliferative disorder (TMD) is a clonal proliferation of megakaryoblasts, typically occurring in newborns with Down syndrome. It is believed that TMD occurs in the presence of GATA1 mutation together with trisomy 21. However, a limited number of patients with TMD but without Down syndrome have been reported, all with a blast population with numeric or rarely structural chromosome 21 abnormalities. We present the first case of a newborn boy with a TMD without trisomy 21 and without any of the mentioned molecular or cytogenetic abnormalities. This case report suggests that unknown disease mechanisms may provoke or mimic TMD. This case report is followed by a concise review of the literature discussing the different entities and pathomechanisms of TMD and acute megakaryocytic leukaemia in patients with or without Down syndrome.     

Acute lymphoblastic leukaemia in children with Down syndrome: an updated review

Down syndrome (DS) is the most common chromosomal abnormality in children and also carries a marked increased incidence of acute leukaemia. Current therapy for acute lymphoblastic leukaemia (ALL) in children with DS offers similar treatment outcome as compared to children without DS. However, in general, there is increased morbidity associated with chemotherapy in children with DS. In recent years, a better understanding of the biology of ALL has led to the elucidation of differences in DS ALL vs non-DS ALL. Further research in these differences may provide a more targeted therapy for DS ALL, with the hopes of continuing good therapeutic outcome while decreasing the toxicities seen in these patients. This review provides an update on the current treatment outcomes and the biological differences seen in DS ALL.     

High positivity of anti-CCP antibodies in patients with Down syndrome

The aim of the present study was to evaluate the prevalence of anti-cyclic citrullinated peptide (CCP) antibodies in patients with Down’s syndrome (DS) previously tested for IgM rheumatoid factor (RF) and to correlate the results with clinical findings. Eighty-eight patients with DS previously tested for IgM-RF were divided into two groups matched for sex and age. Group A consists of 42 RF positive patients and group B of 44 RF negative patients. The presence of anti-CCP antibody was determined using a second-generation enzyme-linked immunosorbent assay. A total of 52.3% (45/86) of DS patients were positive for anti-CCP antibodies. Twenty-four patients (57.1%) of the RF positive group and 21 (47.7%) of the RF negative group presented anti-CCP circulating antibodies. The concordance between both tests was 54.6%. None of the patients had clinical evidence of rheumatoid arthritis or juvenile idiopathic arthritis. Although a high prevalence of anti-CCP antibodies was observed in DS patients, no association has been found presently with clinical disease. Careful follow-up of these patients will be necessary to clarify the real significance of these findings.     

In vivo folic acid supplementation partially corrects in vitro methotrexate toxicity in patients with Down syndrome

Patients with Down syndrome have been found to have characteristic in vivo and in vitro methotrexate toxicity. The in vitro methotrexate toxicity characteristic of Down syndrome can be diminished by the in vivo administration of supplemental high doses of folic acid. A possible explanation for the increased sensitivity to methotrexate which has been documented in patients with Down syndrome may be due to imbalances in nucleotide pools which result from a gene dosage effect and to greater methylation demands. Supplemental folic acid may be beneficial by virtue of a down-regulation of excess gene activity and may also provide needed monocarbons.