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Cells Sep 2022Germline defects in the transcription factor GATA1 are known to cause dyserythropoiesis with(out) anemia and variable abnormalities in platelet count and function....
Germline defects in the transcription factor GATA1 are known to cause dyserythropoiesis with(out) anemia and variable abnormalities in platelet count and function. However, damaging variants closely located to the C-terminal zinc finger domain of GATA1 are nearly unknown. In this study, a 36-year-old male index patient and his 4-year-old daughter suffered from moderate mucocutaneous bleeding diathesis since birth. Whole exome sequencing detected a novel hemizygous missense variant, c.886A>C p.T296P, located between the C-terminal zinc finger and the nuclear localization sequence with non-random X-chromosome inactivation in the heterozygous daughter. Blood smears from both patients demonstrated large platelet fractions and moderate thrombocytopenia in the index. Flow cytometry and electron microscopy analysis supported a combined α-/δ (AN-subtype)-storage pool deficiency as cause for impaired agonist-induced platelet aggregation (light transmission aggregometry) and granule exocytosis (flow cytometry). The absence of BCAM in the index (Lu(a-b-)) and its low expression in the daughter (Lu(a-b+)) confirmed a less obvious effect of defective GATA1 also on erythrocytes. Borderline anemia, elevated HbF levels, and differential transcription of GATA1-regulated genes indicated mild dyserythropoiesis in both patients. Furthermore, a mild SLC4A1 defect associated with a heterozygous c.2210C>T p.A737V variant maternally transmitted in the daughter may modify the disease to mild spherocytosis and hemolysis.
Topics: Anemia; Anion Exchange Protein 1, Erythrocyte; GATA1 Transcription Factor; Hemorrhage; Humans; Male; Phenotype; Platelet Storage Pool Deficiency
PubMed: 36231035
DOI: 10.3390/cells11193071 -
BMC Pediatrics Sep 2022ABO blood group incompatibility, neonatal sepsis, G-6-PD deficiency, thyroid dysfunction, and hereditary spherocytosis are all probable causes of neonatal...
BACKGROUND
ABO blood group incompatibility, neonatal sepsis, G-6-PD deficiency, thyroid dysfunction, and hereditary spherocytosis are all probable causes of neonatal hyperbilirubinemia. However, the etiology of some hyperbilirubinemia is extremely complicated, which may be caused by multiple factors, resulting in severe jaundice. We report a case of severe jaundice due to three causes, showing the significance for the investigation of the etiology of neonatal hyperbilirubinemia.
CASE PRESENTATION
At 96 h of life, a full-term and vaginal delivery male infant with yellowish discoloration of body was transferred to our hospital. When he entered neonatal intensive care unit on the fourth day after birth, he developed jaundice and the transcutaneous bilirubin was 28 mg/dl. Total bilirubin was 540.2 μmol/L, while the indirect bilirubin was 516.7 μmol/L. Both parents and the baby's blood types were O Rh(D +), and direct coomb's test was negative. But mother's indirect coomb's test was positive. Investigating for minor blood group revealed that the father's blood type of Rh was CCDee, the mather's was ccDEE, and CcDEe for the baby. After intensive phototherapy and double volume exchange transfusion, the total bilirubin remained at 303 μmol/L. At day 10, the bilirubin level was 303.5 μmol/L, intensive phototherapy was continued, and intravenous immunoglobulin was used again. The test for thyroid hormones at day 10, the TSH was 13.334mIU/L. And the screening for congenital hypothyroidism showed the TSH was 33mIU/L. Because of the palpable abdominal mass, ultrasound and MRI was done, showed a huge mass in the right adrenal gland. Brainstem auditory evoked potential was performed at day 7, which indicated hearing impairment (65db for left ear and 70db for the right). Euthyrox and intermittent phototherapy were given as following treatment. The jaundice did not subside until the 12th day.
CONCLUSION
Even if their parents' ABO blood group and Rh (d) are consistent, a Coomb test is required for newborns with hyperbilirubinemia since they may have minor blood group incompatibilities. When bilirubin rises rapidly or the clinical treatment effect is inadequate, additional causes should be aggressively screened. Adrenal ultrasound should be performed on newborns with palpable abdominal mass, anemia and jaundice to determine whether there is adrenal hemorrhage.
Topics: Bilirubin; Congenital Hypothyroidism; Female; Hematoma; Humans; Hyperbilirubinemia, Neonatal; Infant, Newborn; Jaundice; Male; Thyrotropin
PubMed: 36089589
DOI: 10.1186/s12887-022-03594-7 -
Romanian Journal of Morphology and... 2022Next to A and B antigens, agglutinogen D exhibits the highest immunogenicity. Following the transfusion of D-positive red blood cells (RBCs), almost 80% of D-negative... (Review)
Review
Next to A and B antigens, agglutinogen D exhibits the highest immunogenicity. Following the transfusion of D-positive red blood cells (RBCs), almost 80% of D-negative recipients develop anti-D antibodies (Abs). Subsequently, anti-D immunization further promotes the synthesis of Abs towards other blood group antigens in or outside the Rh system. The D antigen is also involved in 95% of cases of hemolytic disease of the newborn. Transfusions, hemotherapy, grafts, and obstetric history (abortions, ectopic pregnancy, births) are all risk factors for Rh isoimmunization. In the case of ABO compatibility between mother and fetus, Rh-positive fetal RBCs that have reached the maternal bloodstream are not destroyed by group agglutinins, and Rh antigenic sites are not hidden by the maternal immune system. But a Rh-negative mother with a homozygous Rh-positive husband will certainly have a Rh-positive fetus. As it has an irreversible evolution, the Rh isoimmunization once installed cannot be influenced in the sense of decreasing the Ab titer, therefore, injectable globulin has no effect. A particular case was that of a newborn with Rh system incompatibility associated with hereditary spherocytosis The clinical balance at birth reflects the severe jaundice of the female newborn of 3140 g, gestational age 38∕39 weeks, extracted by lower-segment transverse Caesarean section, with a double loop nuchal cord, Apgar score 8. Because the jaundice was severe and atypical (face and upper chest), we considered the possibility of coexistence of hemolytic disease of the newborn by Rh blood group incompatibility associated with hereditary spherocytosis, as it turned out to be true and mentioned. Changes in genes encoding proteins in the structure of the RBC membrane have amplified hemolysis induced by maternal-fetal isoimmunization in the Rh system. Massive hemolysis accentuated by congenital spherocytosis, confirmed later, imposed blood transfusion and dynamic monitoring.
Topics: Blood Group Incompatibility; Cesarean Section; Female; Hemolysis; Humans; Infant; Infant, Newborn; Jaundice; Pregnancy; Pregnancy Complications; Rh Isoimmunization
PubMed: 36074689
DOI: 10.47162/RJME.63.1.26 -
World Journal of Clinical Cases Jul 2022Neonatal hyperbilirubinemia is a common problem faced by pediatricians. The role of genetic factors in neonatal jaundice has been gradually recognized. This study aims...
BACKGROUND
Neonatal hyperbilirubinemia is a common problem faced by pediatricians. The role of genetic factors in neonatal jaundice has been gradually recognized. This study aims to identify genetic variants that influence the bilirubin level in five patients using next-generation sequencing (NGS).
CASE SUMMARY
Five neonates with severe hyperbilirubinemia were retrospectively studied. They exhibited bilirubin encephalopathy, hypothyroidism, ABO blood type incompatibility hemolysis, glucose-6-phosphate dehydrogenase () deficiency and premature birth, respectively. A customized 22-gene panel was designed, and NGS was carried out for these neonates. Eight variations ( c.G1388A, c.C369G, c.C3825G, c.G211A, c.A1729G, c.G520A, c.1213-4T>G and c.A1474G) were identified in these five neonates. Genetic mutations of these genes are associated with deficiency, thalassemia, Dubin-Johnson syndrome, Gilbert syndrome, hereditary spherocytosis, and hereditary elliptocytosis. One of the neonates was found to have compound variants of the splice site c.1213-4T>G and c.G520A (p.E174K), but no elliptocyte was seen on his blood smear of 4 years old.
CONCLUSION
Pathological factors of severe neonatal hyperbilirubinemia are complicated. Genetic variants may play an important role in an increased risk of neonatal hyperbilirubinemia, and severe jaundice in neonates may be related to a cumulative effect of genetic variants.
PubMed: 36051115
DOI: 10.12998/wjcc.v10.i20.6999 -
EJHaem Aug 2022
PubMed: 36051074
DOI: 10.1002/jha2.520 -
Frontiers in Physiology 2022We investigated by targeted next generation sequencing the genetic bases of hereditary spherocytosis in 25 patients and compared the molecular results with the...
We investigated by targeted next generation sequencing the genetic bases of hereditary spherocytosis in 25 patients and compared the molecular results with the biochemical lesion of RBC membrane obtained by SDS-PAGE analysis. The HS diagnosis was based on available guidelines for diagnosis of congenital hemolytic anemia, and patients were selected because of atypical clinical presentation or intra-family variability, or because presented discrepancies between laboratory investigation and biochemical findings. In all patients but 5 we identified pathogenic variants in genes able to justify the clinical phenotype. Interestingly, a correspondence between the biochemical lesion and the molecular defect was identified in only 11/25 cases, mostly with band 3 deficiency due to mutations. Most of the mutations in and gene didn't hesitate in abnormalities of RBC membrane protein; conversely, in two cases the molecular lesion didn't correspond to the biochemical defect, suggesting that a mutation in a specific cytoskeleton protein may result in a more complex RBC membrane damage or suffering. Finally, in two cases the HS diagnosis was maintained despite absence of both protein defect and molecular lesion, basing on clinical and family history, and on presence of clear laboratory markers of HS. The study revealed complex relationships between the primary molecular lesion and the final effect in the RBC membrane cytoskeleton, and further underlines the concept that there is not a unique approach to the diagnosis of HS.
PubMed: 36035481
DOI: 10.3389/fphys.2022.949044 -
Blood Nov 2022Native circulating blood platelets present with a discoid flat morphology maintained by a submembranous peripheral ring of microtubules, named marginal band. The...
Native circulating blood platelets present with a discoid flat morphology maintained by a submembranous peripheral ring of microtubules, named marginal band. The functional importance of this particular shape is still debated, but it was initially hypothesized to facilitate platelet interaction with the injured vessel wall and to contribute to hemostasis. The importance of the platelet discoid morphology has since been questioned on the absence of clear bleeding tendency in mice lacking the platelet-specific β1-tubulin isotype, which exhibits platelets with a thinner marginal band and an ovoid shape. Here, we generated a mouse model inactivated for β1-tubulin and α4A-tubulin, an α-tubulin isotype strongly enriched in platelets. These mice present with fully spherical platelets completely devoid of a marginal band. In contrast to the single knockouts, the double deletion resulted in a severe bleeding defect in a tail-clipping assay, which was not corrected by increasing the platelet count to normal values by the thrombopoietin-analog romiplostim. In vivo, thrombus formation was almost abolished in a ferric chloride-injury model, with only a thin layer of loosely packed platelets, and mice were protected against death in a model of thromboembolism. In vitro, platelets adhered less efficiently and formed smaller-sized and loosely assembled aggregates when perfused over von Willebrand factor and collagen matrices. In conclusion, this study shows that blood platelets require 2 unique α- and β-tubulin isotypes to acquire their characteristic discoid morphology. Lack of these 2 isotypes has a deleterious effect on flow-dependent aggregate formation and stability, leading to a severe bleeding disorder.
Topics: Mice; Animals; Tubulin; Blood Platelets; Hemostasis; Microtubules; von Willebrand Factor; Blood Coagulation Disorders
PubMed: 36026602
DOI: 10.1182/blood.2022016729 -
Frontiers in Endocrinology 2022Chromosome 8p11.2 includes several key genes in development such as the , , , and genes. Deletion of this fragment causes a contiguous gene syndrome. Currently, few...
BACKGROUND
Chromosome 8p11.2 includes several key genes in development such as the , , , and genes. Deletion of this fragment causes a contiguous gene syndrome. Currently, few cases of interstitial deletion of whole 8p11.2 have been reported. We report a rare case of 8p11.2 deletion syndrome with the unique phenotypes, presenting with early-onset diabetes.
CASE DESCRIPTION
A 20-year-old man with a 1-year history of diabetes mellitus was admitted to the Endocrinology Clinic. Physical examination revealed the dysmorphic facial features, and broad and foreshortened halluces. Laboratory examination indicated spherocytosis anemia, and hypogonadotropic hypogonadism. Bone mineral density analysis showed decreased bone density in the lumbar vertebrae. Brain CT showed calcification. Whole-exome sequencing revealed a 7.05-Mb deletion in 8p11 containing 43 OMIM genes, and a large in-frame deletion of exons 48-55 in the DMD gene. Metformin was given to the patient after which his blood glucose was well controlled. HCG was injected subcutaneously and was supplemented with calcium and vitamin D, which led to an improvement in the patient's quality of life.
CONCLUSION
We report a rare case of 8p11.2 deletion syndrome with unique phenotypes, and early-onset diabetes. It is challenging for endocrinologists to simultaneously reconcile a combination of these diseases across multiple disciplines. We discussed the influencing factors of early-onset diabetes in this patient and speculated that it was caused by complex interactions of known and unknown genetic backgrounds and environmental factors.
Topics: Chromosomes; Diabetes Mellitus; Exons; Humans; Muscular Dystrophy, Duchenne; Quality of Life; Sodium-Phosphate Cotransporter Proteins, Type III; Spherocytosis, Hereditary
PubMed: 35957837
DOI: 10.3389/fendo.2022.914863 -
Experimental and Therapeutic Medicine Sep 2022Hereditary spherocytosis (HS) is an erythrocyte membrane disease with a non-specific phenotype, particularly occurring in neonatal patients, and its diagnosis is...
Hereditary spherocytosis (HS) is an erythrocyte membrane disease with a non-specific phenotype, particularly occurring in neonatal patients, and its diagnosis is challenging. The present study reports on a patient with neonatal HS and reviewed the genetic characteristics of reported neonatal HS cases in China. The patient was admitted only a few hours after birth with jaundice. Auxiliary examination indicated anemia and hyperbilirubinemia. Spherical erythrocytes were occasionally observed in peripheral blood smears. Genetic testing suggested that the patient harbored a novel frameshift mutation (p.Asp495fsTer78) in spectrum, β, erythrocytic (SPTB), which was carried by the father. Review of 160 cases of HS in China revealed 24 to be neonatal cases. In these neonatal cases, the frequency of ankyrin 1 (ANK1) mutations and loss-of-function mutations of pathogenic genes (including ANK1 and SPTB) was higher than that in the non-neonatal group. In conclusion, the present study further expanded the mutation spectrum of SPTB and reaffirms the diagnostic value of gene detection in neonatal HS.
PubMed: 35949318
DOI: 10.3892/etm.2022.11537 -
Eye (London, England) Jun 2023To assess systemic associations of angioid streaks (AS) using a large US healthcare database.
BACKGROUND/OBJECTIVES
To assess systemic associations of angioid streaks (AS) using a large US healthcare database.
SUBJECTS/METHODS
A retrospective cross-sectional study was conducted of patients diagnosed with AS in a large, national US insurer from 2000-2019. Cases were matched 1:5 to controls. The prevalence rates of established associated disease states and other systemic diseases were calculated and compared using logistic regression. Additionally, the rate of anti-VEGF treatment was assessed as a proxy for the incidence of choroidal neovascularization (CNV).
RESULTS
One thousand eight hundred fifty-two cases of AS and 9028 matched controls were included. The rates of association between AS and the well-characterized conditions included: Pseudoxanthoma elasticum (PXE)-228 patients (12.3%), Ehlers-Danlos syndrome-18 patients (1.0%), Paget's disease-6 patients (0.3%), hemoglobinopathies-30 patients (1.6%), and idiopathic-1573 patients (84.9%). There was a statistically higher prevalence of the following less classically associated diseases among patients with AS compared to controls: hereditary spherocytosis (1.7% vs. 0.6%, p < 0.001), connective tissue disease (1.0% vs 0.3%, p < 0.001) and non-exudative age-related macular degeneration (33.9% vs 10.6%, p < 0.001). Among 1442 eligible cases analyzed, 427 (29.6%) received at least 1 anti-VEGF injection with 338 (23.4%) patients having the injection after their AS diagnosis.
CONCLUSIONS
In the largest collection of AS patients to date, the classical teaching of systemic disease associations occur at rates far, far lower than previously reported. The association of AS with other less reported diseases highlights new potential associations and may contribute to the understanding of AS formation.
Topics: Humans; Angioid Streaks; Retrospective Studies; Cross-Sectional Studies; Pseudoxanthoma Elasticum; Choroidal Neovascularization; Delivery of Health Care; Fluorescein Angiography
PubMed: 35915234
DOI: 10.1038/s41433-022-02189-x