Precise diagnosis of a hereditary spherocytosis patient with complicated hematological phenotype.

Hereditary spherocytosis (HS) is one of the most common causes of hereditary hemolytic anemia. The current diagnostic guidelines for HS are mainly based on a combination of physical examination and laboratory investigation. However, some patients present with complicated clinical manifestations that cannot be explained by routine diagnostic protocols. Here, we report a rare HS case of mild anemia with extremely high indirect bilirubin levels and high expression of fetal hemoglobin. Using whole exome sequencing analysis, this patient was identified as a heterozygous carrier of a de novo SPTB nonsense mutation (c.605G > A; p.W202*) and a compound heterozygous carrier of known UGT1A1 and KLF1 mutations. This genetic analysis based on the interpretation of the patient's genomic data not only achieved precise diagnosis by an excellent explanation of the complicated phenotype but also provided valuable suggestions for subsequent appropriate approaches for treatment, surveillance and prophylaxis.

Temporal trends of splenectomy in pediatric hospitalizations with hereditary spherocytosis from 2000 to 2019: A national survey.

BACKGROUND: Total and partial splenectomy are used in pediatric patients with hereditary spherocytosis to resolve anemia and hemolytic complications. PROCEDURE: Data from the Healthcare Cost and Utilization Project's Kid's Inpatient Database was used to profile and describe temporal trends in pediatric (≤18 years) hospital admissions in the United States from 2000 to 2019 data release years. Survey sampling methods were used to produce national estimates. RESULTS: From 2000 to 2019, the use of splenectomy declined overall, from 427 to 206 weighted procedures (difference = 222, 95% confidence interval [CI]: 124-320; p < .0001); the risk of undergoing splenectomy during admission also declined from 56.7% to 38.7% (risk difference = 17.9 percentage points [p.p.], 95% CI: 9.7-26.1; p < .0001). Total splenectomy was mostly used. Age at time of splenectomy increased 10.2 years (difference = 1.6 years, 95% CI: 0.6-2.7; p = .0018). The risk of splenectomy increased with age until 10 years, then leveled off until 18 years. The proportion of children aged ≤5 years undergoing splenectomy decreased from 27.7% to 11.2% in 2019 (risk difference: 16.5 p.p., 95% CI: 7.3-25.7; p = .0004). The strongest clinical predictors of splenectomy, adjusting for patient- and hospital-level characteristics, were a co-diagnosis of symptomatic cholelithiasis (adjusted odds ratio [aOR] = 3.18, 95% CI: 1.92-5.28; p < .0001) and splenomegaly or hypersplenism (aOR = 2.52, 95% CI: 1.74-3.65; p < .0001). Risk of splenectomy with splenomegaly or hypersplenism increased over time. CONCLUSION: Splenectomy was delayed until age greater than 10 years. Older age, co-diagnosis with splenomegaly or hypersplenism, or symptomatic cholelithiasis were strongest clinical predictors of splenectomy. Conservative management of hereditary spherocytosis appears to be more common.

Coinheritance of hereditary spherocytosis with haemochromatosis: next-generation sequencing reveals.

We report the case of a man in his 50s with extravascular haemolysis, fluctuating indirect hyperbilirubinaemia, elevated transferrin saturation with hyperferritinaemia and normal liver enzymes. Spherocytes were detected in a blood smear and a mutation of unknown significance, c.1626+1G>A p.?, in intron 13 of the SLC4A1 gene, was identified by next-generation sequencing (NGS). The same mutation was found in his daughter, who presented with similar laboratory changes, confirming the diagnosis of hereditary spherocytosis. Abdominal MRI showed hepatosplenomegaly with hepatic iron overload. In this context of haemolysis (without anaemia) and iron overload, a diagnosis of haemochromatosis was presumed. NGS confirmed the presence of the variants p.(His63Asp) and p.(Cys282Tyr) in heterozygosity in the HFE gene. We report this case for the rarity of co-existing two haematological diseases counteracting each other.

Severe autoimmune hemolytic anemia complicating hereditary spherocytosis treated successfully with glucocorticoids and cyclosporine: a case report.

BACKGROUND: Severe autoimmune hemolytic anemia complicating hereditary spherocytosis is life threatening and has not been described in a case report. Here, we report a case in which this intractable disease was treated successfully with glucocorticoids and cyclosporine. CASE PRESENTATION: A 25-year-old female patient with hereditary spherocytosis developed severe autoimmune hemolytic anemia after respiratory syncytial virus infection. Her hemoglobin level was 26 g/L and various anti-red blood cell antibodies were detected in her serum, making blood matching difficult. Glucocorticoid monotherapy was ineffective. With the addition of cyclosporine (50 mg/12 h), the patient's hemoglobin level increased significantly and the symptoms associated with anemia were greatly relieved. CONCLUSION: In patients with severe autoimmune hemolytic anemia, especially when the presence of multiple anti-red blood cell antibodies and alloantibodies interferes with blood matching, a glucocorticoid-cyclosporine regimen may be tried.

A de novo ANK1 mutation in a childhood hereditary spherocytosis: a case report.

BACKGROUND: Due to the heterogeneity of the phenotype of Hereditary spherocytosis (HS) patients, some patients may have rare clinical complications such as biliary obstruction and ultra-high bilirubinemia. CASE PRESENTATION: A 8-y-old boy presented to the emergency with complaints of anemia for 6 years and worsened abdominal pain and scleral yellowing of the skin for 2 days. Physical examination showed tenderness in the middle and upper abdomen and splenomegaly. Abdominal CT revealed biliary obstruction. Genetic analysis revealed a de novo mutation in the gene ANK1, HS with biliary obstruction was diagnosed. The surgery of bile duct exploration and T-tube drainage, and splenectomy were performed successively. This patient was followed up for 13 months after splenectomy, and his condition was stable. CONCLUSION: The diagnosis of HS is not clinically difficult, and once a patient with HS is diagnosed, regular follow-up management and standardized treatment are required. Genetic testing is also needed to screen for other genetic disorders that may co-exist in patients with HS who do not have a good efficacy or who have a long-term chronic onset of jaundice.

[Hereditary Spherocytosis and Pregnancy: A Case Report]. / Esferocitose Hereditária e Gravidez: A Propósito de um Caso Clínico.

Even though it is a rare condition, hereditary spherocytosis (EH) is the main inherited cause of haemolytic anaemia and presents with a broad spectrum of symptoms. In the few reported cases of pregnancy and EH, maternal and foetal outcomes are controversial. Particularly, reports of pregnancies with EH associated with thrombosis or portal hypertension are scarce. We present a case of a woman who underwent splenectomy with EH and non-cirrhotic portal hypertension. Our patient presented polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) and plasminogen activator inhibit-1 that have a controversial impact on thrombotic risk. During pregnancy, the woman showed no signs of haemodynamical or cirrhosis deterioration. Concerning the foetus, late-onset foetal growth restriction was diagnosed but did not determine preterm delivery. Five weeks post-partum after an episode of acute abdominal pain, mesenteric venous thrombosis was diagnosed. In this case report, we describe our experience in managing pregnancy, labour and post-partum of a woman with EH, highlighting potential complications of this condition.

A esferocitose hereditária (EH), embora rara, constitui a principal causa de anemia hemolítica hereditária, tendo uma apresentação clínica muito diversa. Raros casos de grávidas com EH estão publicados, tendo um impacto incerto nos desfechos maternos e fetais. Os relatos de gestações complicadas por EH e de complicações trombóticas ou hipertensão portal são particularmente escassos. Apresentamos o caso de uma grávida esplenectomizada, com EH e hipertensão portal não cirrótica. A utente apresentava polimorfismos da metiltetrahidrofolato redutase e fator inibidor do ativador do plasminogénio, mutações com impacto controverso no risco trombótico. Durante a gestação não ocorreu deterioração hemodinâmica ou hepática, diagnosticando-se restrição de crescimento fetal tardia que não condicionou término precoce da gravidez. Cinco semanas após o parto, surgiu um quadro de dor abdominal, tendo-se diagnosticado trombose de veia mesentérica. Descrevemos a nossa experiência de vigilância da gravidez, parto e puerpério de uma mulher com EH grave, com destaque para potenciais complicações associadas à EH.

Treatment of asymptomatic gallstones in children with hereditary spherocytosis requiring splenectomy.

BACKGROUND: Gallstones are common in hereditary spherocytosis (HS) and other chronic hemolytic diseases, with most affected patients being asymptomatic. Whether and how asymptomatic gallstones should be treated is controversial. METHODS: We conducted a retrospective cohort study of pediatric patients with HS and asymptomatic gallstones to compare the clinical outcomes between the observation group (followed up with gallstones in situ) and the intervention group (cholecystectomy or cholecystolithotomy). The primary outcome was the composite of adverse outcomes, including gallstone-associated, gallbladder surgery-associated, and splenectomy-associated events. Secondary outcomes included the changes in the size and number of gallstones and the recurrence of gallstones. RESULTS: Fifty-two patients were included (38 in the observation group and 14 in the intervention group), with a mean follow-up length of 5.2 years. Patients in the intervention group had a lower incidence of primary outcomes (7.1% vs. 42.1%) than patients in the observation group (OR, 0.12; 95%CI, 0.01-0.99). Patients with gallstones >5 mm in diameter had the highest risk of adverse events (47.4%). In the observation group, gallstone growth, disappearance, and stability were observed in 19.4%, 29.0%, and 51.6% of splenectomized HS patients, respectively. Small gallstones (diameter ≤5 mm) or sludge were more likely to be associated with disappearance (P = 0.04). CONCLUSIONS: Most asymptomatic gallstones grow or persist in splenectomized HS patients for an extended period. Surgical treatment of asymptomatic gallstones in HS patients requiring splenectomy is associated with a lower risk of adverse outcomes. LEVELS OF EVIDENCE: III (retrospective comparative study).

Hereditary spherocytosis before and after splenectomy and risk of hospitalization for infection.

BACKGROUND: The infectious burden in hereditary spherocytosis (HS) children before splenectomy has rarely been reported and the risk of severe postsplenectomy infection is controversial. METHODS: We conducted a retrospective study of pediatric patients with HS to evaluate the risk of infection presplenectomy and postsplenectomy. The primary outcome was any bacterial, Mycoplasma, or fungal infection that required hospitalization. The secondary outcomes were sepsis and septic shock. Appendectomized children were matched on age at surgery and enrolled as controls. RESULTS: In all, 232 patients were included. Before splenectomy, the primary outcome was identified in 51 (22.0%) patients, and the secondary outcome was identified in 1 (0.4%) patient. After splenectomy, the primary and secondary outcomes were detected in 8 (4.1%) and 1 (0.5%) patients, respectively. The risk of infection was higher presplenectomy than postsplenectomy (OR, 6.6; 95% CI, 3.0-14.2). HS patients had a higher risk of infection than the controls before surgery (OR, 3.7; 95% CI, 2.3-5.9) but not after surgery (OR, 1.4; 95% CI, 0.6-3.6). CONCLUSIONS: HS patients who require splenectomy later in life had a high incidence of hospitalization for infections. In contrast, postsplenectomy risk of hospitalization involving infection or severe infection was low. IMPACT: Patients with hereditary spherocytosis who require splenectomy later in life have a high risk of hospital admission for infections, especially those with severe hereditary spherocytosis. With vaccines or postoperative antibiotics, splenectomy does not increase the risk of infection or severe infections. Splenectomy may reduce the risk of hospitalization for infections by alleviating the complications of hereditary spherocytosis. With vaccines, prophylaxis, or advanced antibiotics, the benefits of splenectomy in children with hereditary spherocytosis and a heavy disease burden may outweigh the risks.

A Novel SPTA1 Mutation in a Patient with Hereditary Spherocytosis without a Family History and Coexisting Gilbert's Syndrome.

Most patients with hereditary spherocytosis (HS) have a family history of disease, while those without such a history are difficult to diagnose. We herein report a case of HS with no family history harboring a novel heterozygous mutation of SPTA1, c.2161G>A (p.E721K), and a homozygous polymorphism of UGT1A1*6. In silico analyses suggested that the mutation might contribute to the pathogenesis of HS. The coexistence of HS and Gilbert's syndrome increases the risk of gallstones. Therefore, splenectomy, alone or in combination with cholecystectomy, is recommended. The determination of genetic diathesis provides useful information for the management of hemolytic anemia.

[When HbA1c is unreliable : a case report of hereditary spherocytosis]. / Cas clinique. Quand le dosage de l'HbA1c n'est pas fiable : à propos d'un cas de sphérocytose héréditaire.

Glycated haemoglobin (HbA1c) is a biological parameter used in the management of diabetic patients. Independent of the daytime glycaemic variations, but complementary to the measurement of blood glucose or subcutaneous glucose concentrations, it allows both the clinician and the patient to have an appreciation of the glycaemic balance of the last weeks. In this way, anti-diabetic treatment can be adjusted if necessary to achieve the desired goal and hopefully delay or prevent diabetes-related micro- and macroangiopathic complications. Some conditions can alter the glycation of haemoglobin. In this case, the HbA1c level becomes difficult to interpret. Hereditary spherocytosis may be revealed by a dissociation between low HbA1c level and high blood glucose levels. A family history, Coombs-negative haemolytic anaemia, or a finding of spherocytes in the blood smear is suggestive of hereditary spherocytosis. Fructosamine testing may be an alternative. This article will present a patient with hereditary spherocytosis in whom the HbA1c level was not interpretable when compared to the elevated blood glucose measurements.

: L'hémoglobine glyquée (HbA1c) est une valeur biologique utilisée dans le suivi des patients diabétiques. Indépendante de la variation glycémique nycthémérale, mais complémentaire à la mesure de la glycémie ou de la concentration sous-cutanée de glucose, elle permet tant au clinicien qu'au patient d'avoir une appréciation de l'équilibre glycémique des dernières semaines. De cette manière, le traitement anti-diabétique peut être éventuellement adapté pour atteindre l'objectif escompté et espérer retarder, voire prévenir, les complications micro- et macroangiopathiques liées au diabète. Certaines affections peuvent altérer la glycation de l'hémoglobine. Dans ce cas, le taux d'HbA1C devient difficile à interpréter. La sphérocytose héréditaire peut se révéler par un tableau de dissociation entre un taux bas d'HbA1C et des valeurs élevées de glycémie. Des antécédents familiaux, une anémie hémolytique à Coombs négatif, ou une observation de sphérocytes dans le frottis sanguin sont en faveur d'un diagnostic de sphérocytose héréditaire. Le dosage de la fructosamine peut être une alternative. Le présent article abordera le cas d'un patient atteint d'une sphérocytose héréditaire chez qui le taux d'HbA1c n'était pas interprétable en regard des contrôles glycémiques.

A 6-Day-Old Male Infant with Severe Hyperbilirubinemia Diagnosed with Hereditary Spherocytosis at a Tertiary Hospital in East Java, Indonesia: A Diagnostic and Management Challenge in a Developing Country.

BACKGROUND Hereditary spherocytosis (HS) is an autosomal dominant inherited disorder that causes severe hyperbilirubinemia in neonates. There is no factual data about the prevalence in Indonesia. It is common that neonates with suspected hereditary spherocytosis are not diagnosed or treated adequately in developing countries such as Indonesia. CASE REPORT A 6-day-old baby was referred from a secondary public hospital to our tertiary hospital in Malang, East Java with severe hyperbilirubinemia unresponsive to the 2 days of conventional phototherapy. Initial laboratory examination showed total serum bilirubin level 28.83 mg/dL and indirect bilirubin level 25 mg/dL. Complete blood count showed hemoglobin level of 10.3 g/dL with high MCHC 36.9 g/dL and increased RDW 18.7%. The HS ratio (MCHC per MCV) was 0.41. The blood smear showed spherocytes with positive family history from the mother and grandmother. There were no specific tests such as EMA binding, cryohemolysis, or analysis of erythrocyte membrane protein available in our hospital. The patient was then treated with 2 sessions of intensive phototherapy with phototherapy unit bilisphere 360 LED. The total serum bilirubin level dropped to 12.19 mg/dL. In this case, we decided to perform intensive phototherapy first, not only because of facility-based constraints to do timely exchange transfusion, but also due to the low socio-economic and educational background of the parents. CONCLUSIONS There are some challenges in diagnosing and treating HS adequately in Indonesia. Limitations of specific tests, inadequacy of conventional phototherapy, lack of awareness of and adherence to guidelines, and facility-based inability to perform timely exchange transfusion all can contribute to severe hyperbilirubinemia and its sequelae.

Concomitant Hereditary Spherocytosis and Pyruvate Kinase Deficiency in a Spanish Family with Chronic Hemolytic Anemia: Contribution of Laser Ektacytometry to Clinical Diagnosis.

Background: Hereditary spherocytosis (HS) and pyruvate kinase deficiency (PKD) are the most common causes of hereditary chronic hemolytic anemia. Here, we describe clinical and genetic characteristics of a Spanish family with concomitant ß-spectrin (SPTB) c.647G>A variant and pyruvate kinase (PKLR) c.1706G>A variant. Methods: A family of 11 members was studied. Hematological investigation, hemolysis tests, and specific red cell studies were performed in all family members, according to conventional procedures. An ektacytometric study was performed using the osmoscan module of the Lorca ektacytometer (MaxSis. RR Mechatronics). The presence of the SPTB and PKLR variants was confirmed by t-NGS. Results: The t-NGS genetic characterization of the 11 family members showed the presence of a heterozygous mutation for the ß-spectrin (SPTB; c.647G>A) in seven members with HS, three of them co-inherited the PKLR variant c.1706G>A. In the remaining four members, no gene mutation was found. Ektacytometry allowed a clear diagnostic orientation of HS, independently from the PKLR variant. Conclusions: This family study allows concluding that the SPTB mutation, (c.647G>A) previously described as likely pathogenic (LP), should be classified as pathogenic (P), according to the recommendations for pathogenicity of the American College of Medical Genetics and the Association for Molecular Pathology. In addition, after 6 years of clinical follow-up of the patients with HS, it can be inferred that the chronic hemolytic anemia may be attributable to the SPTB mutation only, without influence of the concomitant PKLR. Moreover, only the family members with the SPTB mutation exhibited an ektacytometric profile characteristic of HS.