Glucose-6-phosphate dehydrogenase deficiency with coinherited Gaucher disease: A rare association.

ABSTRACT: Anemia coexisting with Gaucher disease (GD) is often associated with non-hemolytic processes. Few cases of GD with autoimmune hemolytic anemia have been reported. However, literature on GD with concomitant nonimmune hemolytic anemia is scarce. A 1-year 6-month-old male child presented in 2018 with complaints of palpable mass in left upper abdomen, fever, cough, and vomiting. On examination, he had pallor, hepatosplenomegaly of 2 cm and 8 cm below costal margin, respectively. A clinical diagnosis of hemolytic anemia was suspected. Complete blood count revealed Hb---6.7 g/dL, TLC---8.9 × 10 3 /µL, platelet count---180 × 10 3 /µL. Peripheral smear showed predominantly microcytic hypochromic anemia with moderate degree of anisocytosis, many nucleated red blood cells, few schistocytes, polychromatophils and corrected reticulocyte count 7.89%. S. Bilirubin was 1.1 mg/dL. Hb high-performance liquid chromatography (HPLC) of the child and his parents was within normal limit. Hematological work up revealed negative results for direct Coombs' test, osmotic fragility test, and sickling test. Test for Glucose-6-phosphate dehydrogenase deficiency was positive (39 units/trillion RBC, normal 146--376). He was transfused intermittently and given steroids to manage his anemia. He was on regular follow up during which his blood counts revealed persistent anemia and thrombocytopenia. In view of this, bone marrow was performed to exclude myelofibrosis. Aspirate smears were cellular and showed normoblastic erythroid hyperplasia. Numerous large histiocytes with basophilic fibrillary cytoplasm exhibiting "crumpled tissue paper" appearance were seen. Similar findings were seen on bone marrow trephine biopsy. Genetic testing revealed pathogenic variations in the GBA gene. Beta glucosidase enzyme levels were low while chitotriosidase was raised (1109.19 nmol/hr/mL). A final diagnosis of G6PD with GD was made. The present study shows rare association of GD with Glucose-6-phosphate dehydrogenase deficiency.

Neurologic Complications in Patients With Lymphoreticular Malignancy: A Descriptive Cohort Study.

OBJECTIVES: The objectives of this study were to study the spectrum of neurologic complications in children with lymphoreticular malignancy (acute lymphoblastic leukemia, Hodgkin, and non-Hodgkin lymphoma) at diagnosis and during treatment and to determine the etiology of these complications. MATERIALS AND METHODS: In this descriptive cohort study, conducted between November 2018 and March 2020, 204 children with a diagnosis of lymphoreticular malignancy were enrolled. The baseline investigations were done in all the cases. Those who developed neurological symptoms were evaluated with cerebrospinal fluid examination and radiologic and electrophysiologic studies as per indication and were managed according to standard management guidelines. RESULTS: Of the 204 patients, 30 (14.7%) developed neurological complications. The majority of these complications (n=20/30; 87%) occurred during the intensive chemotherapy period. Common complications included acute methotrexate neurotoxicity (n=7), vincristine-induced neurotoxicity (n=7), central nervous system (CNS) relapse (n=4), and posterior reversible encephalopathy syndrome (n=2). L-asparaginase-induced thrombosis (n=1), intramedullary compression syndrome (n=1), CNS infection (n=2), CNS hemophagocytic lymphohistiocytosis (n=1), and steroid-induced myopathy (n=1) were also observed. The complications resolved in 21/30 (70%) patients after receiving appropriate treatment while the neurological complication persisted in 2/30 (6.7%) patients. Three patients (10%) abandoned the treatment, and 4 (13.3%) patients expired. CONCLUSIONS: Neurologic complications in patients with lymphoreticular malignancy are quite variable, having common presenting symptoms but varying imaging abnormalities. By close follow-up and effective treatment, the morbidity and mortality of these complications can be minimized.

Clinico-Hematological Profile and Management of Children With Non-Transfusion Dependent Thalassemia (NTDT) at a Pediatric Center in Northern India.

OBJECTIVE: To study the clinico-hematological profile, complications, and management of children with non-transfusion dependent thalassemia (NTDT) in northern India. METHOD: We retrieved and analyzed the data of 69 children with NTDT diagnosed between January, 2006 to December, 2018, aged under 18 years from our unit's records. RESULTS: The participants mean (SD) age was 4.4 (3.1) years, and they presented with anemia (29%), jaundice (13%), hemolytic facies (13%), splenomegaly (87%), thromboembolism (2.9%) and pathological short stature (28.5%). The most common cause of NTDT was b-thalassemia (45%), followed by either compound-heterozygous or homozygous for Eb-thalassemia mutation. The most frequent single genotype observed was compound heterozygous for IVS1-5 (G>C) and codon 26 (G>A). The mean (SD) follow-up duration was 3.5 (2.4) years. On follow-up, 27 children (%) remained transfusion free, and 30 (%) needed occasional transfusions. 63% of patients initially presenting with pathological short stature showed improvement in growth. Amongst children older than 10 years (n=20), subclinical hypothyroidism was detected in 6 children and impaired glucose tolerance test in 1 child. CONCLUSION: Eß-thalassemia was the commonest cause of NTDT in this population.

Correlation of Transient Elastography With MRI T2* and Serum Ferritin Levels in Children With Transfusion-Dependent Thalassemia.

OBJECTIVES: We investigated the correlation of transient elastography (TE) with MRI R2* values and serum ferritin in patients with transfusion-dependent thalassemia (TDT). METHODS: We reviewed hospital records of 59 patients with TDT aged ³8 years without any evidence of chronic liver disease and who had fibroscan within 3 months of MRI T2*, who seen at our center between January, 2014 and December, 2019. Spearman correlation and linear regression analysis were used to evaluate the correlation between TE liver stiffness measurements and R2* MRI values and with serum ferritin. RESULTS: Mean (SD) age of the subjects was 13.0 (3.1) years and body mass index was 16.6 (2.3) kg/m2. Mean liver stiffness measurement, MRI T2*(3T), corresponding MRI R2*(3T), and ferritin values were 6.55 (3.10) kPa, 3.4 (4.6) milliseconds, 616.20 (383.9) Hz, and 2874.69 (1570.7) ng/mL, respectively. TE measurements correlated with MRI R2* values (r=0.61; P=0.001) and with serum ferritin level (r=0.59, P=0.001). CONCLUSION: TE is a reliable tool to estimate hepatic iron overload in patients with TDT.

COVID-19 pandemic and care of transfusion-dependent patients of thalassaemia: Experience from a paediatric centre in North India.

AIM: COVID-19 has presented an unprecedented challenge to health services and has significantly affected the management of non-Covid illnesses, like thalassemia. The present study documents the impact of Covid-associated restrictions and disruptions on working of the pediatric thalassemia day care centre (TDCC), and measures taken by TDCC and blood transfusion services to adapt to and mitigate the negative impact of Covid pandemic and associated lockdown on patient care. METHODS: Pre-transfusion haemoglobin and packed cell transfusion requirement were compared across three time periods, namely pre-lockdown, lockdown and post-lockdown in paediatric transfusion-dependent thalassaemia (TDT) patients. Caregivers were interviewed to document any problems faced by them. RESULTS: The study involved 181 TDT patients. There was a significant reduction in mean pre-transfusion haemoglobin and red cells transfused during lockdown phase as compared to pre-lockdown phase. Regular care was interrupted in 45% of patients and 76% of patients getting blood from outside could not get leukoreduced red cells. Investigations, monitoring and continuity of iron chelation were also affected. Blood centre faced 30.5% reduction in blood supply during lockdown. TDCC and blood centre took several steps, including prolongation of service hours and staggering of transfusions to ensure maximum transfusions while ensuring social distancing. CONCLUSION: The COVID-19 pandemic imposed many unprecedented challenges to the routine care of thalassaemic patients; however, some of them could be dealt with by a proactive approach and micro-planning at the institution level. Other similar resource-limited settings could learn from experiences for continued quality care for chronic medical conditions during pandemic like situations.

Efficacy and Safety of Thalidomide in Patients With Transfusion-Dependent Thalassemia.

OBJECTIVE: To assess the efficacy and safety of thalidomide in children with transfusion-dependent thalassemia. METHODS: This prospective, single center, open-label study enrolled children aged 12-18 years, and who received thalidomide for a duration of 6 months at a starting dose of 2-3 mg/kg/day. Efficacy was assessed by reduction in transfusion requirement and rate of fall of hemoglobin. Efficacy was classified as major, moderate and minimal/no response depending on the reduction in transfusion requirement. Safety was assessed by adverse effects related to thalidomide. RESULTS: 37 children [mean (SD) age, 14.7 (1.8) years were included. Rate of fall of hemoglobin reduced from a mean of 1.0 (0.24) g/week pre-thalidomide therapy to 0.58 (0.26) g/week after 6 months of thalidomide (P<0.001). 19 children (51.3%) had major response and 12 (32.4%) had moderate response. In 13.5% and 32.4% children response was observed within the first and second month of therapy, respectively. 15 (40.5%) children remained transfusion - free for a median (IQR) time of 6 (3-10) weeks of thalidomide therapy. Mean serum ferritin (SD) decreased from 1758.9 (835.1) to 1549.6(1016.9) (P<0.001). Mean HbF (SD) showed an increase from 2.95(2.6) to 49.2(33.3) (P<0.001). In 32 children, 47 adverse events were observed. Common adverse events were constipation and neutropenia (mostly mild). CONCLUSIONS: Thalidomide resulted in major/moderate response in majority of children with transfusion-dependent thalassemia with satisfactory adverse effect profile.

Pubertal Development and its Determinants in Adolescents With Transfusion-Dependent Thalassemia.

OBJECTIVES: To assess pubertal development and its determinants in adolescents with transfusion-dependent thalassemia (TDT). METHODS: In this cross-sectional study from a tertiary teaching hospital in Delhi, records of adolescents aged 17-19 years with TDT on regular transfusion at thalassemia day-care centre were reviewed. Pubertal development and its determinants were assessed. RESULTS: Records of 58 (33 male) adolescents with TDT were reviewed. Among them, 42 (72.4%) had normal/delayed onset with spontaneous progression of puberty, while 16 (27.6%) had pubertal arrest/failure and received hormonal replacement therapy (HRT). Short stature was observed in all adolescents on HRT. Amongst other endocrinopathies, only hypoparathyroidism was found to be significantly higher in the HRT group. On multivariate analysis, serum ferritin (OR-1.005, 95% CI 1.002, 1.009) was observed to be the only significant determinant of pubertal arrest/failure. CONCLUSIONS: A significant proportion of adolescents with TDT continue to have pubertal arrest/failure. High systemic iron load is the key determinant for this.

Adverse effects with intravenous methotrexate in children with acute lymphoblastic leukemia/lymphoma: a retrospective study.

Methotrexate (MTX) forms the backbone of maintenance cycles in childhood acute lymphoblastic leukemia (ALL) chemotherapy, including interim maintenance. There is sufficient published data describing toxicities of high dose MTX (HD-MTX), but toxicities with escalating doses of MTX (Capizzi regimen) is not well documented. Capizzi regimen is thought to be relatively safe; we contend that even low escalating doses of MTX have significant toxicities. Our study intends to characterise such events with Capizzi MTX in comparison to that seen with HD-MTX. The retrospective study was conducted at a tertiary care centre of North India. We looked for the presence of six main toxicities: febrile neutropenia, thrombocytopenia, mucositis, hepatic toxicity, renal toxicity and skin toxicity from the clinical records of children with newly diagnosed acute lymphoblastic leukemia and lymphoma (intermediate and high risk disease), treated at our centre from November 2013 to July 2018. Intermediate risk ALL (IR-ALL) received Capizzi MTX, whereas high risk ALL (HR-ALL/T-NHL), received HD-MTX. Both these regimens do not use L-asparaginase. A total of 237 cycles of Capizzi escalating MTX and 151 cycles of HD-MTX (B cell: 3 gm/m2 and T cell ALL/T-NHL: 5 gm/m2) during interim maintenance were studied in 93 children. Fifty-four (54) children were of IR (all B cell ALL) and 39 of HR-ALL (21 B-ALL, 18 T-ALL/T-NHL). The combined incidence of toxicities, were similar between the two groups: 68/237 cycles (28.7%) of Capizzi MTX and 45/151 cycles (29.8%) of HD-MTX (P = 0.815). However, mucositis was more commonly witnessed in the later group at 22/151 cycle (14.6%) versus 13/237 cycles (5.5%) in Capizzi MTX (P = 0.002). Nephrotoxicity and skin toxicity was seen only in the HD-MTX group. There was no difference in the severity of toxicity, graded using NCI CTCAE v 5.0, between the two groups. There was no mortality directly attributable to methotrexate toxicity (Grade V toxicity). Serum MTX levels were available in 69/151 (45.7%) cycles of HD-MTX and showed no association with toxicity in this group. Also, there was no difference in the incidence of combined toxicities between groups with (19/69 cycles) or without (26/82 cycles) available serum MTX levels in the HR group (P = 0.577). Male gender, lower baseline ANC and lower BMI had significant association with toxicity. Methotrexate related toxicity is common with both Capizzi and HD-MTX schedule in childhood ALL with a correlation of lower BMI, baseline ANC and male gender. However, it is possible to administer Capizzi as well as HD-MTX in lower middle income countries, with manageable toxicity. Further studies will be required to substantiate our findings and determine the predictors of such events.

Can RBC Indices be Used as Screening Test for Beta-Thalassemia in Indian Antenatal Women?

OBJECTIVE: To determine the appropriateness of using MCV/MCH as screening test for beta-thalassemia trait in the present population and also to find the most appropriate cutoff for optimum sensitivity of these indices. METHODS: It was an analytical, observational and cross-sectional study. Complete blood count followed by high-performance liquid chromatography (HPLC) was performed. The MCV and MCH levels were noted in cases and controls. RESULTS: Thalassemia trait was found in 66 out of 1300 antenatal women with anemia. The MCV and MCH were significantly low in cases (p = 0.0001). MCV had a better AUC (0.650) than MCH (0.635). The most suitable cutoff value of MCV was calculated as 72 fl (sensitivity-63.7%, specificity-68.3%, PPV-9.7%, LR-2.0) and that for MCH was 24 pg (sensitivity-63.6%, specificity-59.4%, PPV-7.7%, LR-1.5) using Youden's index. When MCH (cutoff of 28 pg) and MCV were combined (cutoff of 74 fl), the sensitivity and specificity were 95% and 16%, respectively. CONCLUSION: The sensitivity and specificity of MCV and MCH alone had low detection rate when used in combination had high sensitivity but the specificity was low; therefore, HPLC should be the preferred screening test for beta-thalassemia in Indian women.

Efficacy and Safety of Combined Oral Chelation With Deferiprone and Deferasirox in Children With ß-Thalassemia Major: An Experience From North India.

OBJECTIVE: A combination of desferrioxamine with either deferiprone (DFP) or deferasirox (DFX) for patients with ß-thalassemia major who do not achieve negative iron balance with monotherapy has been studied widely. However, poor compliance resulting from the need for parentral administration of desferrioxamine and its cost necessicitates combining 2 oral chelators. METHODS: A prospective study was conducted in patients with transfusion-dependent ß-thalassemia major in a tertiary care center over 2 years. Patients on either DFP or DFX who were not improving on monotherapy over a long period and persistently maintaining serum ferritin >2500 µg/L were enrolled. Efficacy was assessed by serum ferritin levels assessed at 12 months and 2 years. Complete blood counts and liver and kidney function tests were monitored to assess the safety of the combination of drugs. RESULTS: In total, 33 patients with a mean age of 12.67 years (7.5 to 17.5 y) and a mean ferritin of 4835.2394±1443.85 µg/L formed the study cohort.In total, 28 patients completed the 1-year study period; and 12 patients completed 2 years. Mean serum ferritin reduction at 1 and 2 years was 34.99%±18.13% (range, -34.36% to 56.17%) and 44.67%±13.78% (range, 22.17% to 62.74%), respectively. The combination therapy was well tolerated. CONCLUSIONS: Combined oral chelation with DFP and DFX has better efficacy than either drug used alone. The combination of drugs was well tolerated and no new adverse effects were observed.

Neurological Complications and Cataract in a Child With Thalassemia Major Treated With Deferiprone.

The oral iron chelator deferiprone is associated with various side effects including agranulocytosis, arthropathy, and deranged liver function tests. Rarely, neurological and visual side effects have been reported with high doses. The authors describe rare neurological manifestations of cerebellar ataxia, hypertonia, and bilateral cataract in an 11-year-old boy with thalassemia major on recommended therapeutic doses of deferiprone. The neurological abnormalities resolved with stoppage of deferiprone. Central nervous system toxicity and lenticular opacities may be attributed to the low molecular weight of deferiprone and its ability to cross the blood-brain and blood-ocular barrier, respectively. Clinicians should be alert to the possibility of neurological abnormalities that may occur during deferiprone therapy.