Congenital dyserythropoietic anemia type II (CDAII/HEMPAS): Where are we now?

Congenital diserythropoietic anemias (CDA) were classified according to bone marrow changes and biochemical features 40 years ago. A consistent finding in CDA type II, the most frequent subgroup of CDAs is a relevant hypoglycosylation of erythrocyte membrane proteins. It is a matter of debate if the hypoglycosylation is the primary cause of the disorder or a phenomenon secondary to other pathomechanisms. The molecular cause of the disorder is still unknown although some enzyme deficiencies have been proposed to cause CDA II in the last 2 decades and a linkage analysis locating the CDA II gene in a 5 cM region on chromosome 20 was done in 1997. In this review biochemical and genetic data are discussed and diagnostic methods based on biochemical observations of the recent years are reviewed.     

Congenital dyserythropoietic anaemia (CDA) type I--a case report with ultrastructural study

A case of type-I congenital dyserythropoietic anaemia (CDA) in a Hindu child is described. The clinical and haematological features were characteristic, and the erythroblasts in the bone marrow revealed unusual ultrastructural abnormalities along with ultrastructural abnormalities in platelets and metamyelocytes.     

Ultrastructure of erythroid cells in a case of congenital dyserythropoietic anaemia type II (author's transl)

The ultrastructure of erythroblasts in a case of congenital dyserythropoietic anaemia type II with a negative serum-lysis test is described. The well known symptoms in electronmicroscopy in CDA type I and II are faced to our findings. Morphological changes of hypolemmal cisterns are described and their possible meaning is discussed.     

Cytogenetical and clinical investigations in aplastic anaemia (Fanconi's type)

Summary Cytogenetic investigations were performed in a 10 year-old girl with clinical features of Fanconi's anaemia, i.e.: growth retardation, skin pigmentation, bilateral absence of thumbs, anaemia, leukopenia, etc. A variety of structural anomalies as chromatid gaps and exchanges, chromatid and isochromatid breaks were observed. The same type of chromosome anomalies was found in the parents and in the younger sister of the proposita, the older sister being karyotypically normal.Dermatoglyphic investigations revealed in the proposita the absence of t triradius on both palms and an increased mean ridge count, increased also in all the family members. Genetic implications and possible mechanisms of chromosomal aberrations are discussed.This investigation was supported by a grant from C.N.R., Italy.Professor of Child Health.     

Congenital dyserythropoietic anemia type I: report of a pair of siblings in Japan.

This is the first case of two siblings with congenital dyserythrobpoietic anemia (CDA) type I to be reported from a Japanese family. Both of these cases showed characteristic morphological aberration of erythroid precursors, ineffective erythropoiesis, and negative acidified serum test. The ultrastructural study of erythroblasts also revealed characteristics quite compatible with CDA type I.     

Characterization of the <Emphasis Type="Italic">N</Emphasis>-glycosylation phenotype of erythrocyte membrane proteins in congenital dyserythropoietic anemia type II (CDA II/HEMPAS)

Congenital dyserythropoetic anemia type II (CDA II) is characterized by bi- and multinucleated erythroblasts and an impaired N-glycosylation of erythrocyte membrane proteins. Several enzyme defects have been proposed to cause CDA II based on the investigation of erythrocyte membrane glycans pinpointing to defects of early Golgi processing steps. Hitherto no molecular defect could be elucidated. In the present study, N-glycosylation of erythrocyte membrane proteins of CDA II patients and controls was investigated by SDS-Page, lectin binding studies, and MALDI-TOF/MS mapping in order to allow an embracing view on the glycosylation defect in CDA II. Decreased binding of tomato lectin was a consistent finding in all typical CDA II patients. New insights into tomato lectin binding properties were found indicating that branched polylactosamines are the main target. The binding of Aleuria aurantia, a lectin preferentially binding to α1-6 core-fucose, was reduced in western blots of CDA II erythrocyte membranes. MALDI-TOF analysis of band 3 derived N-glycans revealed a broad spectrum of truncated structures showing the presence of high mannose and hybrid glycans and mainly a strong decrease of large N-glycans suggesting impairment of cis, medial and trans Golgi processing. Conclusion: Truncation of N-glycans is a consistent finding in CDA II erythrocytes indicating the diagnostic value of tomato-lectin studies. However, structural data of erythrocyte N-glycans implicate that CDA II is not a distinct glycosylation disorder but caused by a defect disturbing Golgi processing in erythroblasts.     

Differential sensitivity of Fanconi anaemia lymphocytes to the clastogenic action of cis-diamminedichloroplatinum (II) and trans-diamminedichloroplatinum (II)

Summary Fanconi anaemia (FA) lymphocytes were tested for their susceptibility to chromosomal breakage by cis-diamminedichloroplatinum (II) [cis-Pt(II)] and its stereoisomer trans-diamminedichloroplatinum (II) [trans-Pt(II)]. Unlike trans-Pt(II), which is a rather inefficient clastogen, cis-Pt(II) is very efficient in inducing chromosomal breakage in FA cells at concentrations that hardly affect control cells. As both cis-Pt(II) and trans-Pt(II) are capable of inducing DNA interstrand crosslinks but only cis-Pt(II) can induce DNA intra-strand crosslinks, this result suggests that FA cells may be specifically sensitive to the intrastrand type of DNA crosslink.     

Short rib-polydactyly syndrome,Majewski type,in two male siblings

Summary C-band polymorphisms of chromosomes 1, 9, and 16 were investigated in (1) 165 newborn infants, (2) 93 Down's syndrome patients, (3) 69 patients with acquired mental retardation, (4) 54 idiopathic patients, and (5) 48 idiopathics with multiple congenital malformations. The C-band size of chromosomes 1 and 9 showed a similar nonnormal distribution in all five groups. A significantly higher frequency of C bands, some of which were located on the short arm of chromosome 9, was observed in the groups of patients with Down's syndrome and with idiopathic mental retardation.     

Phenotypic variability of mannosidosis type II: report of two Greek siblings.

Two patients, a 13-year-old boy and his 24-year-old sister, were diagnosed as mannosidosis type II cases, on the basis of both presenting extremely reduced plasma and white blood cell acid-alpha-mannosidase are reported. With the exception of mental retardation and neurosensory deafness the two siblings manifested a wide phenotypic variability. The boy had several facial features indicating a lysosomal storage disorder, as well as spondylolisthesis. His sister, apart from heavy eyebrows and lower jaw prognathism appeared normal.     

Congenital heart disease in sibships ascertained by two affected siblings

Summary Families containing at least 2 children affected by cardiologically diagnosed congential heart disease were selected from the files of the Children's Memorial Hospital, Chicago, Willis J. Potts Children's Heart Center. From the data of 54 such families a recurrence rate of CHD for additional children of between p (K=0, r_(min)=2)=0.0554±0.0256 and p (K=1, r_(min)=2)=0.0801±0.0349 was calculated. Incompleteness of families or voluntary termination of reproduction after the second affected child was born could be excluded as effective bias-inducing factors. In the great majority of cases, sibs displayed identical or closely related malformations. No paternal or maternal age effect was found. Consanguinity was not noticeably increased, but the material was unsuitable for the study of this question. A recurrence rate which was definitely higher in families with at least two affected children than in families selected by a single proband, is taken as further evidence for the importance of genetic factors in congenital heart disease. Any single-gene hypothesis can be fitted to the actual data only if far-reaching additional assumptions are made. A multifactorial genetic system explains the observations more easily. This work has been carried out in part during the author's stay at the Genetic Clinic of the Children's Memorial Hospital, Dept. of Pediatrics, Northwestern University Medical School (Prof. D. Y.-Y. Hsia, M.D.). Data have been collected in collaboration with Dr. M. H. Paul, director of the Dept. of Cardiology of the Children's Memorial Hospital, Willis J. Potts Children's Heart Center. The author was supported in part by a grant from the US Public Health Service, National Institutes of Health and a Fulbright Travel Grant.