Coexistence of hereditary spherocytosis with SPTB P.Trp1150 gene variant and Gilbert syndrome: A case report and literature review.

A congenital protein anomaly in the erythrocyte membrane skeleton causes a hereditary haemolytic illness known as hereditary spherocytosis (HS). The primary characteristic of HS is an increase in the number of tiny spherical red blood cells in the peripheral blood. The chief clinical features of HS include anaemia, jaundice, splenomegaly, spherical erythrocytosis in the blood, chronic anaemia with haemolysis, and recurrent acute attacks. Most patients have a family history; some have autosomal recessive inheritance, whereas most have autosomal dominant inheritance. In cases of severe hyperbilirubinemia disproportionate to haemolysis, other causes of hyperbilirubinemia should be considered. Gilbert syndrome (GS) is an autosomal dominant illness caused by the reduced activity of uridine diphosphate-glucuronosyl transferase lAl and is characterised by intermittent hyperbilirubinemia without any other signs or symptoms of liver disease. The possibility of the coexistence of HS and GS is very limited. Here we present the case of an elderly man with yellow skin and sclera recurring anaemia, and a final diagnosis of coexisting HS and GS.

Complex heterozygous mutations in hereditary spherocytosis: A case report.

BACKGROUND: The aim of this study was to investigate the complex heterozygous mutations of ANK1 and SPTA1 in the same individual and improve our understanding of hereditary spherocytosis (HS) in children. We also hope to promote the application of gene detection technology in children with HS, with the goals of identifying more related gene mutations, supporting the acquisition of improved molecular genetic information to further reveal the pathogenesis of HS in children, and providing important guidance for the diagnosis, treatment, and prevention of HS in children. CASE SUMMARY: A 1-year and 5-month-old patient presented jaundice during the neonatal period, mild anemia 8 months later, splenic enlargement at 1 year and 5 months, and brittle red blood cell permeability. Genetic testing was performed on the patient, their parents, and sister. Swiss Model software was used to predict the protein structure of complex heterozygous mutations in ANK1 and SPTA1. Genetic testing revealed that the patient harbored a new mutation in the ANK1 gene from the father and a mutation in the SPTA1 gene from the mother. Combined with the clinical symptoms of the children, it is suggested that the newly discovered complex heterozygous mutations of ANK1 and SPTA1 may be the cause, providing important guidance for revealing the pathogenesis, diagnosis, treatment, and promotion of gene detection technology in children with HS. CONCLUSION: This case involves an unreported complex heterozygous mutation of ANK1 and SPTA1, which provides a reference for exploring HS.

Hemolysis during open heart surgery in patients with hereditary spherocytosis - systematic review of the literature and case study.

BACKGROUND: Due to the distinctive nature of cardiac surgery, patients suffering from hereditary spherocytosis (HS) are potentially at a high risk of perioperative complications resulting from hemolysis. Despite being the most prevalent cause of hereditary chronic hemolysis, the standards of surgical management are based solely on expert opinion. OBJECTIVE: We analyze the risk of hemolysis in HS patients after cardiac surgery based on a systematic review of the literature. We also describe a case of a patient with hereditary spherocytosis who underwent aortic valve repair. METHODS: This systematic review was registered in the PROSPERO international prospective register of systematic reviews (CRD42023417666) and included records from Embase, MEDLINE, Web of Science, and Google Scholar databases. The case study investigates a 38-year-old patient who underwent surgery for an aortic valve defect in mid-2022. RESULTS: Of the 787 search results, 21 studies describing 23 cases of HS undergoing cardiac surgery were included in the final analysis. Hemolysis was diagnosed in five patients (one coronary artery bypass graft surgery, two aortic valve bioprosthesis, one ventricular septal defect closure, and one mitral valve plasty). None of the patients died in the perioperative period. Also, no significant clinical hemolysis was observed in our patient during the perioperative period. CONCLUSIONS: The literature data show that hemolysis is not common in patients with HS undergoing various cardiac surgery techniques. The typical management of a patient with mild/moderate HS does not appear to increase the risk of significant clinical hemolysis. Commonly accepted beliefs about factors inducing hemolysis during cardiac surgery may not be fully justified and require further investigation.

The coincidence of beta-thalassemia and hereditary spherocytosis: A case report and literature review.

Key Clinical Message: When a person has both HS and beta-thalassemia, their clinical symptoms tend to be less severe. This is because these two conditions have contrasting features. If the clinical symptoms and laboratory results cannot be solely attributed to hemolytic anemia, it is important to consider the possibility of another form of hemolytic anemia coexisting. Abstract: We present a 26-year-old woman who has been experiencing abdominal pain, jaundice, and anemia for the past 15 years. Initially, she was diagnosed with gallstones and splenomegaly, but after a thorough hematology examination conducted by expert colleagues, it was discovered that she had both beta-thalassemia and hereditary spherocytosis. The osmotic fragility test confirmed this diagnosis. The patient was advised to undergo both splenectomy and cholecystectomy procedures. It is worth noting that the co-occurrence of these two conditions is rare.

Catalase, Glutathione Peroxidase, and Peroxiredoxin 2 in Erythrocyte Cytosol and Membrane in Hereditary Spherocytosis, Sickle Cell Disease, and ß-Thalassemia.

Catalase (CAT), glutathione peroxidase (GPx), and peroxiredoxin 2 (Prx2) can counteract the deleterious effects of oxidative stress (OS). Their binding to the red blood cell (RBC) membrane has been reported in non-immune hemolytic anemias (NIHAs). Our aim was to evaluate the relationships between CAT, GPx, and Prx2, focusing on their role at the RBC membrane, in hereditary spherocytosis (HS), sickle cell disease (SCD), ß-thalassemia (ß-thal), and healthy individuals. The studies were performed in plasma and in the RBC cytosol and membrane, evaluating OS biomarkers and the enzymatic activities and/or the amounts of CAT, GPx, and Prx2. The binding of the enzymes to the membrane appears to be the primary protective mechanism against oxidative membrane injuries in healthy RBCs. In HS (unsplenectomized) and ß-thal, translocation from the cytosol to the membrane of CAT and Prx2, respectively, was observed, probably to counteract lipid peroxidation. RBCs from splenectomized HS patients showed the highest membrane-bound hemoglobin, CAT, and GPx amounts in the membrane. SCD patients presented the lowest amount of enzyme linkage, possibly due to structural changes induced by sickle hemoglobin. The OS-induced changes and antioxidant response were different between the studied NIHAs and may contribute to the different clinical patterns in these patients.

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.

Identification of a novel ANK1 gene variant c.1504-9G>A and its mechanism of intron retention in hereditary spherocytosis.

Objective: The objective of this study was to pinpoint pathogenic genes and assess the mutagenic pathogenicity in two pediatric patients with hereditary spherocytosis. Methods: We utilized whole-exome sequencing (WES) for individual analysis (case 1) and family-based trio analysis (case 2). The significance of the intronic mutation was validated through a Minigene splicing assay and supported by subsequent in vitro experiments. Results: Both probands received a diagnosis of hereditary spherocytosis. WES identified a novel ANK1 c.1504-9G>A mutation in both patients, causing the retention of seven nucleotides at the 5' end of intron 13, as substantiated by the Minigene assay. This variant results in a premature stop codon and the production of a truncated protein. In vitro studies indicated a reduced expression of the ANK1 gene. Conclusion: The novel ANK1 c.1504-9G>A variant is established as the causative factor for hereditary spherocytosis, with the c.1504-9G site functioning as a splicing receptor.

A Case Report of Hemolytic Hyponatremia.

Hereditary spherocytosis/elliptocytosis is a non-immune hemolytic anemia caused by an alteration in the erythrocyte membrane that predisposes the cell to its lysis. This report presents a case of a 42-year-old woman with a history of spontaneous abortion, associated with postpartum bleeding, chronic anemia, and premature menopause. After five years, she consulted due to alterations in the state of consciousness and severe symptomatic hyponatremia, with a diagnosis of hypopituitarism, explained by a late Sheehan syndrome. During hospitalization, she developed non-immune hemolytic anemia associated with a positive osmotic fragility test. A diagnosis of hereditary spherocytosis/elliptocytosis was made. We correlate blood hypoosmolarity as a trigger with the in vitro hypotonic solution of the osmotic fragility test for the diagnosis of this disease. This association is not reported in the literature; in our case, we show the concomitant improvement of anemia with the increase in sodium levels and hormonal replacement.

Severe hepatic sinusoidal obstruction syndrome in a patient with Wilms tumor and hereditary spherocytosis.

A 7-year-old girl with a history of splenectomy for hereditary spherocytosis (HS) was diagnosed with renal hematoma after a blunt abdominal trauma while receiving aspirin. Multiple erythrocyte transfusions and transarterial embolization were performed without success. Eventual nephrectomy revealed severely necrotic and perforated Stage III Wilms tumor (WT). Radiochemotherapy was administered, but by the eighth week, she developed severe hepatic sinusoidal obstruction syndrome (HSOS). Her ferritin level at the time was 3406 ng/ml. Defibrotide and aggressive supportive measures provided full recovery. The patient was given deferasirox for iron chelation therapy and finished her treatment without incident. To our knowledge, just one patient with HS and WT has been described in the literature. The role of iron excess in HSOS pathogenesis in non-transplant patients has not been addressed before either. Transfusional hyperferritinemia, in addition to chemotherapeutics and radiation, may have contributed to the development of severe HSOS in our patient.

Reticulocyte Antioxidant Enzymes mRNA Levels versus Reticulocyte Maturity Indices in Hereditary Spherocytosis, ß-Thalassemia and Sickle Cell Disease.

The antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and peroxiredoxin 2 (Prx2) are particularly important in erythroid cells. Reticulocytes and other erythroid precursors may adapt their biosynthetic mechanisms to cell defects or to changes in the bone marrow environment. Our aim was to perform a comparative study of the mRNA levels of CAT, GPX1, PRDX2 and SOD1 in reticulocytes from healthy individuals and from patients with hereditary spherocytosis (HS), sickle cell disease (SCD) and ß-thalassemia (ß-thal), and to study the association between their transcript levels and the reticulocyte maturity indices. In controls, the enzyme mRNA levels were significantly correlated with reticulocyte maturity indices for all genes except for SOD1. HS, SCD and ß-thal patients showed younger reticulocytes, with higher transcript levels of all enzymes, although with different patterns. ß-thal and HS showed similar reticulocyte maturity, with different enzyme mRNA levels; SCD and HS, with different reticulocyte maturity, presented similar enzyme mRNA levels. Our data suggest that the transcript profile for these antioxidant enzymes is not entirely related to reticulocyte maturity; it appears to also reflect adaptive mechanisms to abnormal erythropoiesis and/or to altered erythropoietic environments, leading to reticulocytes with distinct antioxidant potential according to each anemia.

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.

Novel mutation in alpha-spectrin gene in Saudi patients with hereditary spherocytosis.

Hereditary spherocytosis (HS) is the most common hereditary hemolytic disorder induced by red blood cell (RBC) membrane defect. This study was undertaken to determine mutations in genes associated with RBC membrane defect in patients with HS such as α-spectrin gene (SPTA1), ß-spectrin gene (SPTB), ankyrin gene (ANK1), band 3 anion transport gene (SLC4A1) and erythrocyte membrane protein band 4.1 gene (EPB41). Blood samples were collected from 23 unrelated patients with HS. Patients were diagnosed according to the guidelines from the British Society for Hematology. All hematological examinations for the determination of RBC abnormalities and osmotic fragility tests were conducted. Genomic DNA were extracted from peripheral blood cells and coding exons of known genes for hereditary spherocytosis were enriched using Roche/KAPA sequence capture technology and sequenced on an Illumina system via next-generation sequencing (NGS). The data showed that most of the HS patients confirmed splenomegaly and showed elevated reticulocytes and abnormal bilirubin values. NGS analysis identified the heterozygous variant c.5501G > A in the exon 39 of SPTA1 gene, resulted in a Trp1834*, which leads to a premature stop codon and subsequent mRNA degradation (nonsense- mediated decay) or truncation in α spectrin. Moreover, our data also revealed conventional mutations in genes SPTB, ANK, SLC4A1 and EBP41 in severe patients of HS. In short, this is the first report that determined a novel mutation c.5501G > A in SPTA1 gene in the Saudi population. To the best of our knowledge, this variant c.5501G > A has not been described in global literature so far. This novel mutation in SPTA1 gene is unique in the Saudi population.

The Correlation Between Clinical Phenotype and Genotype of Hereditary Spherocytosis.

Objective: Hereditary spherocytosis (HS) is a common hereditary hemolytic disease. This study aimed to explore the correlation between the phenotype and mutant genotype of HS to improve the clinical understanding of HS. Methods: This study reported a case of spontaneous mutation of the ANK1 gene in HS, reviewed previous studies on the genotype-phenotype correlation of HS, statistically analyzed the main types of gene mutations in HS, and summarized the clinical data of patients. Results: This patient had clinical manifestations of anemia, splenomegaly, peripheral blood smear with increased spherocytosis, and bilirubin, confirmed as ANK1 gene mutant HS by gene detection. In addition, this study included 14 previous studies on genotype-phenotype correlation, collected data, and determined that the ANK1 and SPTB genes were the most common types of gene mutations in HS patients. The mutant HS of the ANK1 gene would lead to lower hemoglobin levels. Conclusion: The results of this study showed that ANK1 and SPTB were the most common types of gene mutations in HS patients. Compared with patients with the SPTB genotype HS, patients with ANK1 mutant HS had more severe extravascular hemolysis, and a higher proportion needed splenectomy in early childhood.

Molecular characteristics of hereditary red blood cell membrane disorders in Thailand: a multi-center registry.

Red blood cell (RBC) membrane disorders represent a significant category of hereditary hemolytic anemia; however, information from Southeast Asia is limited. We established a national registry aiming to characterize RBC membrane disorders and their molecular features in Thailand. A total of 100 patients (99 kindreds) diagnosed with RBC membrane disorders between 2011 and 2020 from seven university hospitals were enrolled. The most prevalent disorders observed were hereditary elliptocytosis (HE; n=33), hereditary pyropoikilocytosis (HPP; n=28), hereditary spherocytosis (HS; n=19), Southeast Asian ovalocytosis (SAO; n=10 of 9 kindreds), and two cases of homozygous SAO. The remaining cases were grouped as unclassified membrane disorder. Seventy-six patients (76%) were molecularly confirmed by PCR, direct DNA sequencing, or hi-throughput sequencing. The primary causative gene for HE and HPP was SPTB, accounting for 28 out of 29 studied alleles for HE and 56 of 56 studied alleles for HPP. In the case of HS, dominant sporadic mutations in the ANK1 gene (n=4) and SPTB gene (n=3) were identified as the underlying cause. Notably, the four most common variants causing HE and HPP were SPTB Providence (c.6055 T>C), SPTB Buffalo (c.6074 T>G), SPTB Chiang Mai (c.6224 A>G), and SPTB c.6171__82delins TGCCCAGCT. These recurrent SPTB mutations accounted for 79 out of 84 mutated SPTB alleles (94%). In summary, HE and hereditary HPP associated with recurrent SPTB mutations are the predominant types of RBC membrane disorders observed in Thailand. These findings have significant implications for the clinical management and future research of RBC membrane disorders in the region.

Hereditary Spherocytosis: Can Next-Generation Sequencing of the Five Most Frequently Affected Genes Replace Time-Consuming Functional Investigations?

Congenital defects of the erythrocyte membrane are common in northern Europe and all over the world. The resulting diseases, for example, hereditary spherocytosis (HS), are often underdiagnosed, partly due to their sometimes mild and asymptomatic courses. In addition to a broad clinical spectrum, this is also due to the occasionally complex diagnostics that are not available to every patient. To test whether next-generation sequencing (NGS) could replace time-consuming spherocytosis-specific functional tests, 22 consecutive patients with suspected red cell membranopathy underwent functional blood tests. We were able to identify the causative genetic defect in all patients with suspected HS who underwent genetic testing (n = 17). The sensitivity of the NGS approach, which tests five genes (ANK1 (gene product: ankyrin1), EPB42 (erythrocyte membrane protein band4.2), SLC4A1 (band3), SPTA1 (α-spectrin), and SPTB (ß-spectrin)), was 100% (95% confidence interval: 81.5-100.0%). The major advantage of genetic testing in the paediatric setting is the small amount of blood required (<200 µL), and compared to functional assays, sample stability is not an issue. The combination of medical history, basic laboratory parameters, and an NGS panel with five genes is sufficient for diagnosis in most cases. Only in rare cases, a more comprehensive functional screening is required.

Case report: Genetic analysis of a novel intronic inversion variant in the SPTB gene associated with hereditary spherocytosis.

Background: Hereditary spherocytosis (HS) is a congenital haemolytic anaemia attributed to dysregulation or abnormal quantities of erythrocyte membrane proteins. Currently, the most common erythrocytic gene, spectrin ß (SPTB), variants are located in exons and give rise to mRNA defects. However, the genetic characteristics and pathogenic mechanisms of SPTB intronic variants are not completely understood. This study aimed to analyse a rare intronic inversion variant in the SPTB gene associated with HS, and explore the impact of the variant on SPTB mRNA splicing. Method: The clinical manifestations of the patient were summarised and analysed for spherocytosis phenotype diagnosis. The pathogenic variant was identified in the proband using targeted next-generation and Sanger sequencing. RNA sequencing was performed to analyse whether SPTB gene splicing and expression were affected. Results: Targeted next-generation sequencing identified a novel disease-associated intronic inversion variant of the SPTB gene in the proband. The inversion variant was located between intron 19 and 20, and contained the entire exon 20 and partial sequences of adjacent introns. Sanger sequencing confirmed that the intronic inversion variant only appeared in the genome of the proband, not in his parents. RNA sequencing revealed that the variant could result in the skipping of exon 20 and reduced expression of SPTB mRNA. Conclusion: This study identifies a rare intronic inversion variant in the SPTB gene associated with hereditary spherocytosis. The pathogenic variant can lead to exon 20 skipping and decreased SPTB gene expression. This finding has not been previously reported in any literature. This study can expand the intronic variant spectrum of the SPTB gene, deepen our understanding of HS pathogenesis, and contribute to the genetic diagnosis and clinical management of patients.

[Hemolytic anemia in a two-year-old child: A case of multiple red blood cell abnormalities]. / Anémie hémolytique chez un enfant de deux ans : Un cas d'anomalies multiples du globule rouge.

The discovery of hemolytic anemia requires a meticulous investigation to determine its etiology. Among patients of African origin, it is not uncommon to find multiple constitutional red blood cell abnormalities, which can complicate diagnosis. We herein describe the case of a two-year-old child presenting with acute hemolytic anemia. A G6PD deficiency, hereditary spherocytosis, and a sickle cell trait A/S were simultaneously identified, all within the context of a primary infection with Parvovirus B19. This virus commonly triggers acute anemia in children exhibiting constitutional red blood cell abnormalities and need to be considered in such cases.

Integrative preimplantation genetic testing analysis for a Chinese family with hereditary spherocytosis caused by a novel splicing variant of SPTB.

Hereditary spherocytosis (HS), the most common inherited hemolytic anemia disorder, is characterized by osmotically fragile microspherocytic red cells with a reduced surface area on the peripheral blood smear. Pathogenic variants in five erythrocyte membrane structure-related genes ANK1 (Spherocytosis, type 1; MIM#182900), SPTB (Spherocytosis, type 2; MIM#616649), SPTA1 (Spherocytosis, type 3; MIM#270970), SLC4A1 (Spherocytosis, type 4; MIM#612653) and EPB42 (Spherocytosis, type 5; MIM#612690) have been confirmed to be related to HS. There have been many studies on the pathogenic variants and mechanisms of HS, however, studies on how to manage the transmission of HS to the next-generation have not been reported. In this study, we recruited a patient with HS. Targeted next-generation sequencing with a panel of 208 genes related to blood system diseases detected a novel heterozygous variant in the SPTB: c.300+2dup in the proband. Sanger sequencing of variant alleles and haplotype linkage analysis of single nucleotide polymorphism (SNP) based on next-generation sequencing were performed simultaneously. Five embryos were identified with one heterozygous and four not carrying the SPTB variant. Single-cell amplification and whole genome sequencing showed that three embryos had varying degrees of trisomy mosaicism. One of two normal embryos was transferred to the proband. Ultimately, a healthy boy was born, confirmed by noninvasive prenatal testing for monogenic conditions (NIPT-M) to be disease-free. This confirmed our successful application of PGT in preventing transmission of the pathogenic variant allele in the HS family.

[Clinical and genotypic analysis of hereditary spherocytosis combined with cholestasis among pediatric patients].

Objective: To understand the clinical and genetic characteristics of hereditary spherocytosis (HS) combined with cholestasis among pediatric patients. Methods: 12 cases of HS children accompanied by cholestasis at Hunan Children's Hospital were selected as the research subjects between January 2013 and December 2022. Clinical data were collected. Whole-exome sequencing was performed by second-generation sequencing. Suspected pathogenic mutation sites were verified by Sanger sequencing. Results: All pediatric patients were admitted to the hospital due to their yellow skin tone. Eight cases (66.67%) had a positive family history. The clinical manifestations were jaundice, splenomegaly (12/12), abdominal pain, anemia (4/12), and hepatomegaly (5/12). All pediatric patients had decreased hemoglobin, an increased reticulocyte ratio, total bilirubin and direct bilirubin, a positive erythrocyte fragility test, and remarkable spherical erythrocytes in their peripheral blood. Seven cases had elevated aminotransferase; four cases had severely elevated aminotransferase and bilirubin; eight cases had biliary calculi; and two cases had a dilated biliary tract. Liver pathological examination showed mild damage to the liver cells (G1S1) in three pediatric cases. Five children had a total of six unreported mutations: SPTB gene c.2431_2450del, c.4974-2A > G, c.2575G > A, and exon 22-35 deletion; ANK1 gene: c.2379-2380delC; and c .6dupC. Children still had abnormal bilirubin levels following treatment. Two pediatric cases underwent splenectomy. Bilirubin and hemoglobin levels returned to normal after surgery. Conclusion: Children with HS may experience cholestasis, and those with poor treatment results may consider undergoing a splenectomy. Six new types of variants have expanded the HS gene mutation spectrum.