ABSTRACT
We describe the second patient with anionic exchanger 1/band 3 null phenotype (band 3 nullVIENNA ), which was caused by a novel nonsense mutation c.1430C>A (p.Ser477X) in exon 12 of SLC4A1. We also update on the previous band 3 nullCOIMBRA patient, thereby elucidating the physiological implications of total loss of AE1/band 3. Besides transfusion-dependent severe hemolytic anemia and complete distal renal tubular acidosis, dyserythropoiesis was identified in the band 3 nullVIENNA patient, suggesting a role for band 3 in erythropoiesis. Moreover, we also, for the first time, report that long-term survival is possible in band 3 null patients.
Subject(s)
Acidosis, Renal Tubular/etiology , Anemia, Hemolytic/etiology , Anion Exchange Protein 1, Erythrocyte/genetics , Codon, Nonsense/genetics , Erythrocytes, Abnormal/pathology , Acidosis, Renal Tubular/pathology , Anemia, Hemolytic/pathology , Child, Preschool , Erythropoiesis , Homozygote , Humans , Male , PrognosisABSTRACT
We report two children with severe chronic hemolytic anemia, the cause of which was difficult to establish because of transfusion dependency. Reduced erythrocyte pyruvate kinase activity in their asymptomatic parents provided the diagnostic clues for mutation screening of the PKLR gene and revealed that one child was a compound heterozygote of a novel paternally derived 5-bp deletion in the promoter region (c.-88_-84delTCTCT) and a maternally derived missense mutation in exon nine (c.1174G>A; p.Ala392Thr). The second child was a compound heterozygote of two novel missense mutations, namely a paternally derived exon ten c.1381G>A (p.Glu461Lys) and a maternally derived exon seven c.907-908delCC (p.Pro303GlyfsX12) variant.
Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic , Anemia, Hemolytic , Base Sequence , Blood Transfusion , Exons , Mutation, Missense , Promoter Regions, Genetic , Pyruvate Kinase/deficiency , Pyruvate Kinase/genetics , Pyruvate Metabolism, Inborn Errors , Sequence Deletion , Anemia, Hemolytic/genetics , Anemia, Hemolytic/therapy , Anemia, Hemolytic, Congenital Nonspherocytic/genetics , Anemia, Hemolytic, Congenital Nonspherocytic/therapy , Child, Preschool , Female , Humans , Male , Pyruvate Metabolism, Inborn Errors/genetics , Pyruvate Metabolism, Inborn Errors/therapy , Transfusion ReactionABSTRACT
BACKGROUND: Hypothalamic-pituitary (HP) disease is the most common CNS manifestation of Langerhans cell histiocytosis (LCH) frequently leading to diabetes insipidus (DI) and anterior pituitary hormone deficiencies (APD). On MRI, loss of the normal posterior pituitary signal and thickening of the pituitary stalk have been described, as well as neurodegenerative signal changes associated with neuropsychological disabilities in some patients. The influence of therapy on the long-term course of HP tumors and neurodegeneration (ND) is not well-understood. PROCEDURE: In this retrospective survey we focused on patients with LCH and HP disease with clinical and MRI data available at diagnosis of HP disease and at least three follow up investigations. We collected clinical and MRI follow-up information for central review and analysis. RESULTS: We identified 22 patients with HP tumors (HPT) registered at the LCH study center. Many different treatment regimens were applied for variable periods, with more than one regimen in most patients. Regression of the tumor was seen in the majority, but all patients had APD or ND on MRI at last follow up. In none of the patients APD and ND regressed or resolved. A deterioration of radiological ND was noted in 17 patients leading to overt clinical neuropsychological impairment in five. CONCLUSIONS: Patients with HPT appear to be at high risk to develop permanent neuroendocrine consequences. Coordinated studies for patients with LCH and HP disease including thorough MRI monitoring and neuropsychological tests are needed.
