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.

Hemophagocytic lymphohistiocytosis associated with parvovirus B19-induced aplastic crisis in a hereditary spherocytosis patient: A case report and literature review.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation. It occurs because of severe inflammation due to uncontrolled proliferation of activated lymphocytes and histiocytes, characterized by the production of excessive levels of cytokines. Virus-associated HLH is a well-known entity, and parvovirus B19 is one of the common causes. Parvovirus B19 can also affect blood cell lineages. Therefore, HLH may be accompanied by several diseases such as cytopenia, aplastic anemia, and myelodysplastic syndrome. Herein, we report the case of a patient with hereditary spherocytosis who was diagnosed with parvovirus B19-induced HLH and aplastic crisis. A 7-year-old girl presented to our hospital with fever, pleural effusion, pancytopenia, hepatosplenomegaly, and hypotension. A bone marrow biopsy was performed under the suspicion of HLH, which revealed hemophagocytes. The diagnostic criteria for HLH were met, and prompt chemoimmunotherapy was initiated considering the clinically unstable situation. Her health improved rapidly after initiating treatment. Further study revealed that she had hereditary spherocytosis, and parvovirus B19 had caused aplastic crisis and HLH. The patient's clinical progress was excellent, and chemoimmunotherapy was reduced and discontinued at an early stage. This case shows that aplastic crisis and HLH can coexist with parvovirus B19 infection in patients with hereditary spherocytosis. Although the prognosis was good in this case of HLH caused by parvovirus B19, early detection and active treatment are essential.

Diagnosis and clinical management of red cell membrane disorders.

Heterogeneous red blood cell (RBC) membrane disorders and hydration defects often present with the common clinical findings of hemolytic anemia, but they may require substantially different management, based on their pathophysiology. An accurate and timely diagnosis is essential to avoid inappropriate interventions and prevent complications. Advances in genetic testing availability within the last decade, combined with extensive foundational knowledge on RBC membrane structure and function, now facilitate the correct diagnosis in patients with a variety of hereditary hemolytic anemias (HHAs). Studies in patient cohorts with well-defined genetic diagnoses have revealed complications such as iron overload in hereditary xerocytosis, which is amenable to monitoring, prevention, and treatment, and demonstrated that splenectomy is not always an effective or safe treatment for any patient with HHA. However, a multitude of variants of unknown clinical significance have been discovered by genetic evaluation, requiring interpretation by thorough phenotypic assessment in clinical and/or research laboratories. Here we discuss genotype-phenotype correlations and corresponding clinical management in patients with RBC membranopathies and propose an algorithm for the laboratory workup of patients presenting with symptoms and signs of hemolytic anemia, with a clinical case that exemplifies such a workup.

Neonatal hereditary spherocytosis caused by a de novo frameshift mutation of the SPTB gene characterized by hydrops fetalis: A case report.

RATIONALE: The etiology of non-immune hydrops fetalis is complex, and its prognosis is poor. One of its main causes is anemia. There are few reports on hydrops fetalis due to anemia caused by hereditary spherocytosis (HS), especially regarding its occurrence in the neonatal period. Thus, we report on a case of neonatal HS caused by a new SPTB gene mutation that was characterized by hydrops fetalis. PATIENT CONCERNS: A neonate with intrauterine hydrops fetalis showed severe hyperbilirubinemia and anemia, reticulocytosis, and hepatosplenomegaly. Laboratory examination findings were normal. DIAGNOSES: Gene sequencing of the patient and his parents showed a de novo frameshift mutation in the patient's SPTB gene. Ultimately, the patient was diagnosed with HS. INTERVENTIONS: Exchange and red blood cell transfusions were performed in the neonatal period. OUTCOMES: The child was discharged from the hospital 14 days postnatal because his hemoglobin and bilirubin levels were stable. Red blood cell transfusion was performed once in infancy; however, no further red blood cell transfusions were required within 2 years of age. LESSONS: Hydrops fetalis can be a manifestation of HS. Genetic detection can help confirm the diagnosis of suspected neonatal HS undocumented by other laboratory examinations.

Vasculo-toxic and pro-inflammatory action of unbound haemoglobin, haem and iron in transfusion-dependent patients with haemolytic anaemias.

Increasing evidence suggests that free haem and iron exert vasculo-toxic and pro-inflammatory effects by activating endothelial and immune cells. In the present retrospective study, we compared serum samples from transfusion-dependent patients with ß-thalassaemia major and intermedia, hereditary spherocytosis and sickle cell disease (SCD). Haemolysis, transfusions and ineffective erythropoiesis contribute to haem and iron overload in haemolytic patients. In all cohorts we observed increased systemic haem and iron levels associated with scavenger depletion and toxic 'free' species formation. Endothelial dysfunction, oxidative stress and inflammation markers were significantly increased compared to healthy donors. In multivariable logistic regression analysis, oxidative stress markers remained significantly associated with both haem- and iron-related parameters, while soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble endothelial selectin (sE-selectin) and tumour necrosis factor α (TNFα) showed the strongest association with haem-related parameters and soluble intercellular adhesion molecule 1 (sICAM-1), sVCAM-1, interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) with iron-related parameters. While hereditary spherocytosis was associated with the highest IL-6 and TNFα levels, ß-thalassaemia major showed limited inflammation compared to SCD. The sVCAM1 increase was significantly lower in patients with SCD receiving exchange compared to simple transfusions. The present results support the involvement of free haem/iron species in the pathogenesis of vascular dysfunction and sterile inflammation in haemolytic diseases, irrespective of the underlying haemolytic mechanism, and highlight the potential therapeutic benefit of iron/haem scavenging therapies in these conditions.

Genotype-phenotype correlation in children with hereditary spherocytosis.

Hereditary spherocytosis (HS) is a common inherited haemolytic anaemia attributed to disturbances in five different red cell membrane proteins. We performed a retrospective study of 166 children with HS and describe the clinical phenotype according to the genotype. In 160/166 (97%) children with HS a disease-causing mutation was identified. Pathogenic variants in ANK1, SPTB, SLC4A1 and SPTA1 were found in 49%, 33%, 13% and 5% of patients. Children with SLC4A1-HS had the mildest phenotype, showing the highest haemoglobin (P < 0·001), lowest reticulocyte counts (P < 0·001) and lowest unconjugated bilirubin levels (P = 0·006), and none required splenectomy in childhood (P < 0·001). Conversely, children with autosomal recessive SPTA1-HS had the most severe clinical phenotype, with almost all patients undergoing splenectomy in early childhood. Patients with ANK1 and SPTB variants showed a similar clinical phenotype. Within each gene, variant type or location did not predict disease severity or likelihood of splenectomy. Among patients with a genetic diagnosis, 47 (29%) underwent splenectomy (23 partial; 24 total) while 57 (36%) underwent cholecystectomy. Total splenectomy led to greater improvements in haemoglobin (P = 0·02). Select use of genetic testing (especially in patients without a family history) may help predict clinical phenotype in childhood and guide family counselling.

[Hereditary spherocytosis in the experience of two pediatric clinics from Targu Mures]. / Herediter spherocytosis a marosvásárhelyi gyermekhematológia osztály tapasztalatában.

Introduction: Hereditary spherocytosis is a genetically determined familial hemolytic anemia. Clinically it is ranged from an asymptomatic condition to severe hemolytic anemia. The major complications are aplastic or megaloblastic crisis, hemolytic crisis, cholecystitis and cholelithiasis. Aim: To shortly summarize the most characteristic symptoms of hereditary spherocytosis from the prism of our centers in order to help primary care-physicians or pediatricians in this affection recognition. Method: In our retrospective study, we processed a period of 6 years between 2012-2017, we studied the clinical signs, laboratory and imagistical findings, evolution and complications. Results: In this period, 47 cases were admitted with hereditary spherocytosis diagnosis to our departments. The most frequent symptoms were jaundice, hepato- and splenomegaly. The observed complications were: hemolytic crisis, aplastic crisis, cholecystitis and cholelithiasis. Conclusion: The main diagnostic elements are anamnesis, clinical signs, laboratory findings and anamnestic data. Early diagnosis is extremely important in order to provide substitution therapy and correct imagistic and hematologic controls. Orv Hetil. 2019; 160(45): 1798-1803.

A de novo ANK1 mutation associated to hereditary spherocytosis: a case report.

BACKGROUND: Hereditary spherocytosis (HS) is a type of hemolytic anemia caused by abnormal red cell membrane skeletal proteins with few unique clinical manifestations in the neonate and infant. An ANK1 gene mutation is the most common cause of HS. CASE PRESENTATION: The patient was a 11-month-old boy who suffered from anemia and needed a regular transfusion therapy at an interval of 2-3 months. Hematological investigations showed moderate anemia (Hb80 g/L). Red cells displayed microcytosis (MCV76.4 fl, MCH25.6 pg, MCHC335 g/L). The reticulocytes were elevated (4.8%) and the spherocytes were increased (10%). Direct antiglobulin test was negative. Biochemical test indicated a slight elevation of bilirubin, mainly indirect reacting (TBIL32.5 µmol/L, IBIL24 µmol/L). The neonatal HS ratio is 4.38, obviously up the threshold. Meanwhile, a de novo ANK1 mutation (exon 25:c.2693dupC:p.A899Sfs*11) was identified by next-generation sequencing (NGS). Thus, hereditary spherocytosis was finally diagnosed. CONCLUSIONS: Gene detection should be considered in some hemolytic anemia which is difficult to diagnose by routine means. We identified a novel de novo ANK1 heterozygous frameshift mutation in a Yi nationality patient while neither of his parents carried this mutation.

Hereditary spherocytosis: Retrospective evaluation of 65 children.

Güngör A, Yarali N, Fettah A, Ok-Bozkaya I, Özbek N, Kara A. Hereditary spherocytosis: Retrospective evaluation of 65 children. Turk J Pediatr 2018; 60: 264-269. Hereditary spherocytosis (HS) is a common cause of congenital hemolytic anemia in Caucasians and it could be diagnosed at any age. The aim of this study is to examine the demographic characteristics, clinical features and laboratory findings of children with HS and their complications observed during follow up. Sixty-five patients, with hereditary spherocytosis between January 2008 and September 2013, were enrolled into this retrospective study. The age of patients at the time of diagnosis varied between 15 days and 17 years. The median age of patients at diagnosis was 48 months (IQR 2-78). The female/male ratio was 1.1. Forty-seven patients (72.3%) had a family history of HS. The patients were classified according to laboratory findings: 13 of them (20%) were diagnosed as mild HS, 36 (55.4%) as moderate HS and of 16 (24.6%) as severe HS. During follow-up, nine patients (13.8%) experienced an aplastic crisis. Megaloblastic crisis was not observed in any patient. Twenty patients (30.8%) had cholelithiasis. Splenectomy was performed in 20% of patients and the mean age for splenectomy was 8.3 years. Complications such as sepsis or thrombosis were not detected after splenectomy. Hereditary spherocytosis should be kept in mind in patients with anemia, jaundice and splenomegaly and the family history must be questioned. The most common complication was gallstone; even patients without severe hemolysis should be followed intermittently by abdominal ultrasonography in order to control the development of gallstone.

Inherited hemolytic anemia: a possessive beginner's guide.

Significant advances have been made in diagnosis and clinical management of inherited red cell membrane disorders that result in hemolytic anemia. Membrane structural defects lead to hereditary spherocytosis (HS) and hereditary elliptocytosis (HE), whereas altered membrane transport function accounts for hereditary xerocytosis (HX) and hereditary overhydrated stomatocytosis (OHS). The degrees of membrane loss and resultant increases in cell sphericity determine the severity of anemia in HS and HE, and splenectomy leads to amelioration of anemia by increasing the circulatory red cell life span. Alterations in cell volume as a result of disordered membrane cation permeability account for reduced life span red cells in HX and OHS. Importantly, splenectomy is not beneficial in these 2 membrane transport disorders and is not recommended because it is ineffective and may lead to an increased risk of life-threatening thrombosis. Rational approaches are now available for the diagnosis and management of these inherited red cell disorders, and these will be discussed in this review.

Hereditary Spherocytosis in the Neonatal Period: A Case Report.

Hereditary spherocytosis (HS) is the third most common yet most frequently underrecognized, congenitally acquired hemolytic disease of the neonate. Hereditary spherocytosis is caused by a defect of one or more erythrocyte membrane proteins, which leads to an increased rate of destruction of circulating red blood cells. The HS spectrum of symptoms is varied from asymptomatic to intrauterine hydrops. Diagnostic tests range from a complete blood count (CBC) analysis to deoxyribonucleic acid (DNA) sequencing. Management in the neonatal period focuses primarily on associated comorbidities, including the prevention of severe hyperbilirubinemia and anemia. Life span implications of HS include hemolysis, jaundice, anemia, splenomegaly, and periodic gallstones. Early identification and diagnosis of HS is essential to ensure proper monitoring and medical management throughout infancy, childhood, and adulthood.

Red cell membrane disorders.

Significant advances have been made in our understanding of the structural basis for altered cell function in various inherited red cell membrane disorders with reduced red cell survival and resulting hemolytic anemia. The current review summarizes these advances as they relate to defining the molecular and structural basis for disorders involving altered membrane structural organization (hereditary spherocytosis [HS] and hereditary elliptocytosis [HE]) and altered membrane transport function (hereditary overhydrated stomatocytosis and hereditary xerocytosis). Mutations in genes encoding membrane proteins that account for these distinct red cell phenotypes have been identified. These molecular insights have led to improved understanding of the structural basis for altered membrane function in these disorders. Weakening of vertical linkage between the lipid bilayer and spectrin-based membrane skeleton leads to membrane loss in HS. In contrast, weakening of lateral linkages among different skeletal proteins leads to membrane fragmentation and decreased surface area in HE. The degrees of membrane loss and resultant increases in cell sphericity determine the severity of anemia in these two disorders. Splenectomy leads to amelioration of anemia by increasing the circulatory red cell life span of spherocytic red cells that are normally sequestered by the spleen. Disordered membrane cation permeability and resultant increase or decrease in red cell volume account for altered cellular deformability of hereditary overhydrated stomatocytosis and hereditary xerocytosis, respectively. Importantly, splenectomy is not beneficial in these two membrane transport disorders and in fact contraindicated due to severe postsplenectomy thrombotic complications.