Variable clinical severity of hereditary spherocytosis: Relation to erythrocytic spectrin concentration, osmotic fragility, and autohemolysis

doi:10.1016/S0022-3476(05)81081-9

The Journal of Pediatrics

Volume 117, Issue 3, September 1990, Pages 409-416

https://doi.org/10.1016/S0022-3476(05)81081-9 Get rights and content

To determine whether stratifying hereditary spherocytosis by degree of severity could provide guldelines regarding which patients would benefit from splenectomy, we evaluated the clinical characteristics of 80 patients (63 children) and 27 healthy relatives. In addition to routine hematologic determinations, osmotic fragility, autohemolysis, erythrocyte spectrin content, and erythrocyte membrane lipid phoshorus were measured and correlated with the disease severity. Four categories were identified: (1) spherocytosis as a trait in symptom-free relatives of patients with recesslvely inherited disease; (2) mild and (3) moderate spherocytosis, largely observed in patients with dominantly inherited disease; and (4) severe spherocytosis, observed in only two patients, who were characterized by recessive inheritance and transfusion dependence. By the identification of carriers, a recessive mode of inheritance could be demonstrated in 20% of the families with spherocytosis. The erythrocyte spectrin concentration was normal in carriers and patients with mild spherocytosis, and was significantly reduced in the moderate and severe states of the disease. This difference was not accounted for by reduced membrane area of the cells, as measured by the phospholipid concentration per cell. We conclude that patients with mild spherocytosis usually do not require splenectomy during childhood and adolescence; patients with moderate or severe disease should have splenectomy. Patients with severe spherocytosis have a partial response to splenectomy but a considerable degree of increased hemolysis persists. Most patients with less than 80% of normal spectrin content require splenectomy.

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Hematology of childhood and adolescence
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Hematologic homeostasis requires an intricate interaction of red blood cells, white blood cells, platelets, and coagulation factors. Normal parameters vary with age, sex, and race. Underlying causes for hematologic abnormalities in children may range from common benign phenomena such as self-limited cytopenias following viral infections, to rarer and more life-threatening entities like childhood acute lymphoblastic leukemia. Overlapping presenting features among these disorders demand thoughtful analysis and clinical acumen. Early recognition and intervention can often minimize complications and decrease long-term morbidity and mortality. In the majority of cases, diagnosis and management of these conditions will require consultation with a pediatric hematologist. Non-malignant quantitative and qualitative hematologic disorders are discussed in this section and have been curated with a general pediatric audience in mind. Given the relatively large number of disorders and the broad scope of the chapter, tables have been utilized to provide lists of disorders within categories, and not all disorders are discussed within the text.
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In this chapter, we introduce the concept of hemolytic anemia and classify them into corpuscular defects due to abnormalities in membrane, enzymes, or hemoglobin and extracorpuscular defects due to immune, acquired and mechanical hemolytic anemias.
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SPTB related spherocytosis in a three-generation family presenting with kidney failure in adulthood due to co-occurrence of UMOD disease causing variant
2020, Nefrologia
Hereditary spherocytosis is clinically and genetically heterogeneous disorder and its clinical characteristics are spherocytosis, anaemia, jaundice and splenomegaly. The aetiology is associated to the genes encoding proteins involved in the interaction between the erythrocyte membrane and the lipid bilayer. Causative variants in βI-spectrin (SPTB) gene presenting as mild to moderately severe disease are responsible for approximately 25% cases in the USA and Europe. Among kidney disease, isolated cases of nephrotic syndrome due to membranoproliferative glomerulonephritis and macroscopic haematuria with proteinuria due to IgA nephropathy were previously reported in patients with SPTB deficiency.
Seven patients from the same family with spherocytosis were evaluated to assess the kidney failure presented in all affected adult patients.
Clinical, radiological and laboratory investigations were issued to evaluate the spherocytosis and kidney disease. In selected patients, we also performed genetics testing with next generation sequencing of genes related to hereditary spherocytosis, inherited glomerular disorders and tubulo-interstitial kidney disease.
Among the family members with spherocytosis, two adults had end-stage kidney disease and one chronic kidney disease stage 4 with unspecific histopathological findings of interstitial fibrosis/tubular atrophy and glomerulosclerosis. At the time, there were no signs of kidney disease present in four paediatric patients. Novel nonsense variant in SPTB gene (NM_001024858; c.4796G>A; p.Trp1599Ter) was detected in all family members with spherocytosis and was predicted to be disease causing. Furthermore, all adult patients with kidney failure and two paediatric cousins of the index patients were heterozygous for the UMOD gene variant (NM_003361.3:c.552G>C, NP_003352.2:p.Trp184Cys) previously reported in patients with tubulo-interstitial kidney disease. UMOD variant was not present in the index patients.
The co-occurrence of any two rare inherited disorders is extremely rare, while to our knowledge the co-occurrence of genetically confirmed HS and autosomal dominant tubulo-interstitial kidney disease (ADTKD) has previously not been reported. It is not possibly to evaluate whether the haemolytic crises due to HS are influencing the progression of the UMOD related renal disease, since the UMOD related ADTKD characteristics in general and in here presented family are extremely variable. Nevertheless, the observed kidney disease in the family is warranting the regular nephrological examinations in UMOD positive paediatric patients in the family in order to recognise hyperuricemia and treat it as early as possible. This is emphasising the importance of serum uric acid detection in routine laboratory screening of paediatric patients in order to identify early signs of tubular injury indicating possible ADTKD.
La esferocitosis hereditaria es un trastorno clínica y genéticamente heterogéneo, y sus características clínicas son esferocitosis, anemia, ictericia y esplenomegalia. Su etiología se asocia con los genes que codifican proteínas implicadas en la interacción entre la membrana de los eritrocitos y la bicapa lipídica. Las variantes causativas en el gen de la espectrina βI (SPTB) que se presentan como enfermedad entre leve y moderadamente grave son responsables de aproximadamente el 25% de los casos en EE.UU. y Europa. En el contexto de la enfermedad renal se han notificado casos aislados de síndrome nefrótico debido a glomerulonefritis membranoproliferativa y hematuria macroscópica con proteinuria debido a nefropatía por IgA en pacientes con deficiencia de SPTB.
Se estudió a 7 pacientes pertenecientes a una misma familia con esferocitosis para evaluar la insuficiencia renal presente en todos los pacientes adultos afectados.
Se realizaron investigaciones clínicas, radiológicas y analíticas para evaluar la esferocitosis y la nefropatía. En una selección de pacientes también se realizaron análisis genéticos mediante técnicas de secuenciación de nueva generación de genes relacionados con la esferocitosis hereditaria, los trastornos glomerulares hereditarios y la nefropatía tubulointersticial.
Entre los miembros de la familia con esferocitosis 2 adultos presentaban nefropatía en fase terminal y uno nefropatía crónica de fase 4, con hallazgos histopatológicos inespecíficos de fibrosis intersticial/atrofia tubular y glomeruloesclerosis. En ese momento no existían signos de enfermedad renal en 4 pacientes pediátricos. Se detectó una nueva variante sin sentido en el gen SPTB (NM_001024858; c.4796G>A; p.Trp1599Ter) en todos los miembros de la familia con esferocitosis y se predijo que era responsable de la enfermedad. Además, todos los pacientes adultos con insuficiencia renal y 2 pacientes pediátricos primos de los pacientes iniciales eran heterocigóticos para la variante del gen UMOD (NM_003361.3:c.552G>C, NP_003352.2:p.Trp184Cys) notificada previamente en los pacientes con nefropatía tubulointersticial. Los pacientes iniciales no presentaban la variante UMOD.
La presentación conjunta de cualquiera de estos 2 trastornos hereditarios poco frecuentes es extraordinariamente excepcional, mientras que hasta donde alcanza nuestro conocimiento la presentación conjunta de esferocitosis hereditaria y nefropatía tubulointersticial autosómica dominante (ADTKD) no se había notificado previamente. No es posible evaluar si las crisis hemolíticas debidas a la esferocitosis hereditaria influyen en la progresión de la nefropatía relacionada con el gen UMOD, ya que las características de la ADTKD relacionada con el gen UMOD, en general y en la familia objeto del estudio, son extremadamente variables. Sin embargo, la nefropatía observada en la familia aconseja realizar exploraciones nefrológicas regulares en los pacientes pediátricos positivos para UMOD de la familia, con el objetivo de reconocer la hiperuricemia y tratarla lo antes posible. Esto enfatiza la importancia de la detección del ácido úrico sérico en las pruebas analíticas rutinarias de los pacientes pediátricos para identificar síntomas tempranos de lesiones tubulares indicativas de una posible ADTKD.
Splenectomy for Conditions Other Than Trauma
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Chemical Transport Knockout for Oxidized Vitamin C, Dehydroascorbic Acid, Reveals Its Functions in vivo
2017, EBioMedicine
Citation Excerpt :
RBCs from mice raised on bromoAA had a right shifted osmotic fragility curve and a significantly shifted 50% lysis NaCl concentration, when compared to RBCs from gulo−/− mice raised on ascorbate and to wildtype mice (Fig. 2D). Hereditary spherocytosis has similar osmotic fragility changes with fresh blood as performed here, and these changes are physiologically relevant (Eber et al., 1990). Oxygen-hemoglobin dissociation (p50) was measured in RBCs from WT mice; and from gulo−/− without ascorbate, with ascorbate, and with bromoAA.
Despite its transport by glucose transporters (GLUTs) in vitro, it is unknown whether dehydroascorbic acid (oxidized vitamin C, DHA) has any in vivo function. To investigate, we created a chemical transport knockout model using the vitamin C analog 6-bromo-ascorbate. This analog is transported on sodium-dependent vitamin C transporters but its oxidized form, 6-bromo-dehydroascorbic acid, is not transported by GLUTs. Mice (gulo^−/−) unable to synthesize ascorbate (vitamin C) were raised on 6-bromo-ascorbate. Despite normal survival, centrifugation of blood produced hemolysis secondary to near absence of red blood cell (RBC) ascorbate/6-bromo-ascorbate. Key findings with clinical implications were that RBCs in vitro transported dehydroascorbic acid but not bromo-dehydroascorbic acid; RBC ascorbate in vivo was obtained only via DHA transport; ascorbate via DHA transport in vivo was necessary for RBC structural integrity; and internal RBC ascorbate was essential to maintain ascorbate plasma concentrations in vitro/in vivo.
Spleen histology in children with sickle cell disease and hereditary spherocytosis: hints on the disease pathophysiology
2017, Human Pathology
Citation Excerpt :
This causes moderate to severe splenomegaly, which is typically associated with anemia, reticulocytosis, jaundice, and increased risk of gallstones. Splenectomy improves HS-related symptoms in most cases [6,9]. SCD is a hereditary disorder caused by a point mutation on the β-globin gene, inducing a glutamic acid–to-valine substitution at position 6 [10].
Hereditary spherocytosis (HS) and sickle cell disease (SCD) are associated with splenomegaly and spleen dysfunction in pediatric patients. Scant data exist on possible correlations between spleen morphology and function in HS and SCD. This study aimed to assess the histologic and morphometric features of HS and SCD spleens, to get possible correlations with disease pathophysiology. In a large series of spleens from SCD, HS, and control patients, the following parameters were considered: (i) macroscopic features, (ii) lymphoid follicle (LF) density, (iii) presence of perifollicular marginal zones, (iv) presence of Gamna-Gandy bodies, (v) density of CD8-positive sinusoids, (vi) density of CD34-positive microvessels, (vii) presence/distribution of fibrosis and smooth muscle actin (SMA)–positive myoid cells, and (viii) density of CD68-positive macrophages. SCD and HS spleens had similar macroscopic features. SCD spleens had lower LF density and fewer marginal zones than did HS spleens and controls. SCD also showed lower CD8-positive sinusoid density, increased CD34-positive microvessel density and SMA-positive myoid cells, and higher prevalence of fibrosis and Gamna-Gandy bodies. HS had lower LF and CD8-positive sinusoid density than did controls. No significant differences were noted in red pulp macrophages. By multivariate analysis, most HS spleens clustered with controls, whereas SCD grouped separately. A multiparametric score could predict the degree of spleen changes irrespective of the underlying disease. In conclusion, SCD spleens display greater histologic effacement than HS, and SCD-related changes suggest impaired function due to vascular damage. These observations may contribute to guide the clinical management of patients.

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^*: Supported by grant No. Eb 99/1-1 from the Deutsche Forschungsgemeinschaft.

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Original articleVariable clinical severity of hereditary spherocytosis: Relation to erythrocytic spectrin concentration, osmotic fragility, and autohemolysis*

Blood

Am J Med

J Pediatr

Blood

Anal Biochem

J Lipid Res

Anal Biochem

Clin Haematol

Genetics of spherocytosis

Am J Hum Genet

Deficient red cell spectrin in severely recessively inherited hereditary spherocytosis

N Engl J Med

Partial deficiency of erythrocyte spectrin in hereditary spherocytosis

Nature

Inheritance pattern and clinical response to splenectomy as a reflection of erythrocyte spectrin deficiency in hereditary spherocytosis

N Engl J Med

A genetic defect in the binding of spectrin in a kindred with hereditary spherocytosis

N Engl J Med

Abnormal oxidant sensitivity and beta-chain structure of spectrin in hereditary spherocytosis associated with defective spectrin-protein 4.1 binding

J Clin Invest

Original article
Variable clinical severity of hereditary spherocytosis: Relation to erythrocytic spectrin concentration, osmotic fragility, and autohemolysis*