Severe congenital hemolytic anemia caused by a novel compound heterozygous PKLR gene mutation in a Chinese boy

The article presents retrospective data analysis of a cohort of patients with PKD (n = 41 patients, aged 4 months – 26,5 years, median of age – 5 years 1 month) who were examined at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology for unspecifid hereditary hemolytic anemia during the period 2013–2020. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. In all patients, the diagnosis was confimed by Next Generation sequencing (NGS). The homozygous mutations in the PKLR gene were found in 10 patients (24.39%), compound heterozygous mutations in 31 patients (75.61%), 77.78% of them were missense mutations. Gender distribution (male:female) was 1:1.73. At least once transfusion of erythrocyte suspension was required to 40 (97.56%) patients. The minimum age at the time of the debut of transfusion dependence was the fist day of life, the maximum was 4 years. Exchange blood transfusion was performed in 13 children, severe normocytic hyperregenerative anemia with transfusion of red blood cells in the fist days of life was noted in 12 children, at the 1st month of life – in 9 children, at the 2nd month of life – in 8 children, at the 3rd month – in 6 children, at the 5th month – in 2 children, at the 1st year – in 1 child, and 2 children underwent single transfusions on the background of infectious episodes at 3 and 4 years respectively. Splenectomy due to high transfusion dependence was performed in 10 patients: transfusion independence was achieved in 5 patients, in 5 – an increase in the interval between blood transfusions. Median of surgical intervention (9 patients): 7 years 4 months, minimum age – 1 year 4 months, maximum – 14 years 4 months. In total, 36 genotypes were described in 41 patients, among them were: c.1529G>A in 3 patients, c.1137_1139del / c.1456C>T – in 2 patients, c.1079G>A/c.1529G>A in 2 patients, c.1130T>C/c.1456C>T in 2 patients, other genotypes occurred once. Two mutations were the most frequent: c.1456C>T (16.67%) and c.1529G>A (16.67%). 19 (46,34%) of patients had previously not described mutations.

Download Full-text

Nephrotic-Range Proteinuria and Peripheral Edema in a Child: Not Only Idiopathic Nephrotic Syndrome

Case Reports in Nephrology and Dialysis ◽

10.1159/000449423 ◽

2016 ◽

Vol 6 (3) ◽

pp. 120-127 ◽

Cited By ~ 3

Author(s):

Valentina Dolcemascolo ◽

Marina Vivarelli ◽

Manuela Colucci ◽

Francesca Diomedi-Camassei ◽

Rossella Piras ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Gene Mutation ◽

Hemolytic Anemia ◽

Shiga Toxin ◽

Alternative Pathway ◽

Disease Onset ◽

Simultaneous Occurrence ◽

Cerebral Microvessels ◽

Peripheral Edema ◽

Nephrotic Range Proteinuria

Hemolytic uremic syndrome (HUS) is defined by the simultaneous occurrence of hemolytic anemia, thrombocytopenia, and acute kidney injury due to thrombotic microangiopathy (TMA) mainly occurring in renal and cerebral microvessels. Although the most common cause of HUS in children is Shiga toxin-producing Escherichia coli, atypical forms in which Shiga toxin is not the trigger may occur. Research over the last few years has shown that complement dysregulation secondary to mutations of genes coding for proteins involved in the regulation of the alternative pathway of complement account for most forms of atypical HUS (aHUS). Among these, thrombomodulin (THBD) gene mutations, representing 3–5% of all alternative pathway complement component abnormalities, correlate with early disease onset and rapid evolution to end-stage renal failure. aHUS onset is generally sudden, but occasionally the only manifestations of renal TMA are arterial hypertension, proteinuria, and a progressive increase in serum creatinine. Nephrotic syndrome at disease onset is exceptional. We describe the case of an adolescent female who presented with peripheral edema due to nephrotic-range proteinuria with bioptic evidence of TMA. Study of the alternative complement pathway showed a heterozygous missense THBD gene mutation (P501L variant) consistent with aHUS diagnosis. One year later she developed clinical signs of hemolytic anemia. Eculizumab, an anti-C5 monoclonal antibody, was started with rapid improvement. This case report highlights the phenotypic variability in aHUS due to THBD gene mutation. Early diagnosis by renal biopsy followed by genetic screening is required to optimize management in such a rare disease with a severe prognosis.

Download Full-text

Congenital Hemolytic Anemia with High Sodium, Low Potassium Red Cells

New England Journal of Medicine ◽

10.1056/nejm196803142781101 ◽

1968 ◽

Vol 278 (11) ◽

pp. 573-581 ◽

Cited By ~ 83

Author(s):

Harold S. Zarkowsky ◽

Frank A. Oski ◽

Ramadan Sha'afi ◽

Stephen B. Shohet ◽

David G. Nathan

Keyword(s):

Hemolytic Anemia ◽

Red Cells ◽

High Sodium ◽

Low Potassium ◽

Congenital Hemolytic Anemia

Download Full-text

Studies on active and passive cation fluxes in congenital hemolytic anemia with high sodium and low potassium erythrocytes

Pediatric Research ◽

10.1203/00006450-197411000-00037 ◽

1974 ◽

Vol 8 (11) ◽

pp. 900-900 ◽

Cited By ~ 2

Author(s):

W Schröter ◽

K Ungefehr

Keyword(s):

Hemolytic Anemia ◽

High Sodium ◽

Low Potassium ◽

Congenital Hemolytic Anemia

Download Full-text

Clinical and hematologic outcomes after splenectomy for congenital hemolytic anemia

Journal of Current Medical Research and Practice ◽

10.4103/jcmrp.jcmrp_119_19 ◽

2021 ◽

Vol 6 (1) ◽

pp. 41

Author(s):

RaniaR El Nahal ◽

MostafaM Embaby ◽

MotazA El Tayeb ◽

MohammedH Ghazaly

Keyword(s):

Hemolytic Anemia ◽

Congenital Hemolytic Anemia

Download Full-text

Life-Threatening Extrarenal Manifestations in an Infant with Atypical Hemolytic Uremic Syndrome Caused by a Complement 3-Gene Mutation

Kidney & Blood Pressure Research ◽

10.1159/000502289 ◽

2019 ◽

Vol 44 (5) ◽

pp. 1300-1305

Author(s):

Sa Ra Han ◽

Myung Hyun Cho ◽

Jin Soo Moon ◽

Il Soo Ha ◽

Hae Il Cheong ◽

...

Keyword(s):

Gastrointestinal Bleeding ◽

Hemolytic Uremic Syndrome ◽

Gene Mutation ◽

Hemolytic Anemia ◽

Atypical Hemolytic Uremic Syndrome ◽

Pulmonary Hemorrhage ◽

Microangiopathic Hemolytic Anemia ◽

Life Threatening ◽

Uremic Syndrome ◽

Extrarenal Manifestations

Background: Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment caused by uncontrolled activation of the complement system. About 20% of patients show extrarenal manifestations, with central nervous system involvement being the most frequent. We described the clinical course and management of aHUS in an infant, that was caused by a complement 3 (C3) gene mutation with severe extrarenal manifestations. Case Presentation: A 4-month-old girl visited our hospital for jaundice and petechiae. Laboratory tests revealed microangiopathic hemolytic anemia, thrombocytopenia, and hyperazotemia. She was diagnosed with aHUS with a C3 p.E1160K mutation. Daily fresh-frozen plasma (FFP) therapy was administered; however, she experienced the severe extrarenal manifestations of pulmonary hemorrhage and gastrointestinal bleeding. With aggressive treatment, supportive care, and daily FFP transfusion, the patient recovered and was discharged after 72 days of hospital stay, on a regular FFP transfusion. Four months after diagnosis, she was switched to eculizumab treatment. Twenty months have passed since then and she has been relapse-free until now. Conclusion: aHUS is rare but has a devastating course if not properly treated. Severe extrarenal manifestations, such as pulmonary hemorrhage and gastrointestinal bleeding, can develop in aHUS caused by a C3 mutation. In our case, long-term management with eculizumab resulted in relapse-free survival.

Download Full-text