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Congenital dyserythropoietic anemia type 4(CDAN4)

MedGen UID:
462276
Concept ID:
C3150926
Disease or Syndrome
Synonyms: ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE IVa; CDA, TYPE IVa; Congenital dyserythropoietic anemia, type IV
SNOMED CT: Congenital dyserythropoietic anemia type IV (719453009); Congenital dyserythropoietic anemia type 4 (719453009)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): KLF1 (19p13.13)
 
Monarch Initiative: MONDO:0013355
OMIM®: 613673
Orphanet: ORPHA293825

Definition

Congenital dyserythropoietic anemia type IVa (CDAN4A) is an autosomal dominant red blood cell disorder characterized by ineffective erythropoiesis and hemolysis resulting in anemia. Circulating erythroblasts and erythroblasts in the bone marrow show various morphologic abnormalities. Affected individuals with CDAN4A also have increased levels of fetal hemoglobin (summary by Arnaud et al., 2010). For a discussion of genetic heterogeneity of congenital dyserythropoietic anemia, see CDAN1 (224120). [from OMIM]

Clinical features

From HPO
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Weight loss
MedGen UID:
853198
Concept ID:
C1262477
Finding
Reduction of total body weight.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
Simultaneous enlargement of the liver and spleen.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Hemolytic anemia
MedGen UID:
1916
Concept ID:
C0002878
Disease or Syndrome
A type of anemia caused by premature destruction of red blood cells (hemolysis).
Erythroid hyperplasia
MedGen UID:
4536
Concept ID:
C0014800
Disease or Syndrome
Increased count of erythroid precursor cells, that is, erythroid lineage cells in the bone marrow.
Reticulocytosis
MedGen UID:
60089
Concept ID:
C0206160
Finding
An elevation in the number of reticulocytes (immature erythrocytes) in the peripheral blood circulation.
Anisocytosis
MedGen UID:
66371
Concept ID:
C0221278
Finding
Abnormally increased variability in the size of erythrocytes.
Poikilocytosis
MedGen UID:
67451
Concept ID:
C0221281
Finding
The presence of abnormally shaped erythrocytes.
Persistence of hemoglobin F
MedGen UID:
68693
Concept ID:
C0239941
Finding
Hemoglobin F (HbF) contains two globin alpha chains and two globin gamma chains. It is the main form of hemoglobin in the fetus during the last seven months of intrauterine development and in the half year of postnatal life. In adults it normally makes up less than one percent of all hemoglobin. This term refers to an increase in HbF above this limit. In beta thalassemia major, it may represent over 90 percent of all hemoglobin, and in beta thalassemia minor it may make up between 0.5 to 4 percent.
Schistocytosis
MedGen UID:
576247
Concept ID:
C0344386
Laboratory or Test Result
The presence of an abnormal number of fragmented red blood cells (schistocytes) in the blood.
Anemia of inadequate production
MedGen UID:
95937
Concept ID:
C0392708
Pathologic Function
A kind of anemia characterized by inadequate production of erythrocytes.
Reduced hematocrit
MedGen UID:
1630955
Concept ID:
C0744727
Finding
A reduction below the normal ratio of the volume of red blood cells to the total volume of blood.
Increased RBC distribution width
MedGen UID:
1630967
Concept ID:
C0948014
Finding
Red blood cell distribution width (RDW) is a simple parameter of the standard full blood count and a measure of heterogeneity in the size of circulating erythrocytes. It is provided by automated hematology analyzers and it reflects the range of the red cell size. It is calculated by dividing the standard deviation of erythrocyte volume by the mean corpuscular volume (MCV) and multiplied by 100 to convert to a percentage.
Decreased hemoglobin concentration
MedGen UID:
1670936
Concept ID:
C4732750
Finding
An abnormal reduction below normal hemoglobin concentration in the circulation.
Circulating nucleated red blood cells
MedGen UID:
1785393
Concept ID:
C5539477
Finding
The presence of nucleated red blood cells in the peripheral blood circulation.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Wide anterior fontanel
MedGen UID:
400926
Concept ID:
C1866134
Finding
Enlargement of the anterior fontanelle with respect to age-dependent norms.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Unconjugated hyperbilirubinemia
MedGen UID:
82786
Concept ID:
C0268306
Disease or Syndrome
An increased amount of unconjugated (indirect) bilurubin in the blood.
Hyperbilirubinemia
MedGen UID:
86321
Concept ID:
C0311468
Finding
An increased amount of bilirubin in the blood.
Increased circulating lactate dehydrogenase concentration
MedGen UID:
1377250
Concept ID:
C4477095
Finding
An elevated level of the enzyme lactate dehydrogenase in the blood circulation.
Reduced haptoglobin level
MedGen UID:
1686017
Concept ID:
C5209264
Finding
An abnormally low concentration of haptoglobin in the blood circulation. Decreased haptoglobin in conjunction with increased reticulocyte count and anemia may indicate hemolysis. Decreased haptoglobin levels can also occur in the absence of hemolysis, due to cirrhosis of the liver, disseminated ovarian carcinomatosis, pulmonary sarcoidosis, and elevated estrogen state.
Hydrops fetalis
MedGen UID:
6947
Concept ID:
C0020305
Disease or Syndrome
The abnormal accumulation of fluid in two or more fetal compartments, including ascites, pleural effusion, pericardial effusion, and skin edema.
Hypothyroidism
MedGen UID:
6991
Concept ID:
C0020676
Disease or Syndrome
Deficiency of thyroid hormone.

Professional guidelines

PubMed

Bianchi P, Schwarz K, Högel J, Fermo E, Vercellati C, Grosse R, van Wijk R, van Zwieten R, Barcellini W, Zanella A, Heimpel H
Br J Haematol 2016 Nov;175(4):696-704. Epub 2016 Jul 29 doi: 10.1111/bjh.14271. PMID: 27471141
Chrobák L
Acta Medica (Hradec Kralove) 2006;49(3):193-5. PMID: 17117609

Recent clinical studies

Etiology

Zaninoni A, Fermo E, Vercellati C, Marcello AP, Barcellini W, Bianchi P
Front Immunol 2020;11:1309. Epub 2020 Jun 23 doi: 10.3389/fimmu.2020.01309. PMID: 32655575Free PMC Article
Resnitzky P, Shaft D, Shalev H, Kapelushnik J, Dgany O, Krasnov T, Tamary H
Eur J Haematol 2017 Oct;99(4):366-371. Epub 2017 Aug 29 doi: 10.1111/ejh.12931. PMID: 28755517
Wickramasinghe SN, Wood WG
Br J Haematol 2005 Nov;131(4):431-46. doi: 10.1111/j.1365-2141.2005.05757.x. PMID: 16281933
Iolascon A, Delaunay J, Wickramasinghe SN, Perrotta S, Gigante M, Camaschella C
Blood 2001 Aug 15;98(4):1258-60. doi: 10.1182/blood.v98.4.1258. PMID: 11493480
Perrotta S, del Giudice EM, Carbone R, Servedio V, Schettini F Jr, Nobili B, Iolascon A
J Pediatr 2000 Apr;136(4):556-9. doi: 10.1016/s0022-3476(00)90026-x. PMID: 10753261

Diagnosis

Maisonneuve E, Ben M'Barek I, Leblanc T, Da Costa L, Friszer S, Pernot F, Thomas P, Castaigne V, Toly N'Dour C, Mailloux A, Cortey A, Jouannic JM
Fetal Diagn Ther 2020;47(2):156-164. Epub 2019 Sep 10 doi: 10.1159/000501554. PMID: 31505487
Resnitzky P, Shaft D, Shalev H, Kapelushnik J, Dgany O, Krasnov T, Tamary H
Eur J Haematol 2017 Oct;99(4):366-371. Epub 2017 Aug 29 doi: 10.1111/ejh.12931. PMID: 28755517
Wickramasinghe SN, Wood WG
Br J Haematol 2005 Nov;131(4):431-46. doi: 10.1111/j.1365-2141.2005.05757.x. PMID: 16281933
Iolascon A, Delaunay J, Wickramasinghe SN, Perrotta S, Gigante M, Camaschella C
Blood 2001 Aug 15;98(4):1258-60. doi: 10.1182/blood.v98.4.1258. PMID: 11493480
Perrotta S, del Giudice EM, Carbone R, Servedio V, Schettini F Jr, Nobili B, Iolascon A
J Pediatr 2000 Apr;136(4):556-9. doi: 10.1016/s0022-3476(00)90026-x. PMID: 10753261

Therapy

Rangarajan HG, Stanek JR, Abdel-Azim H, Modi A, Haight A, McKinney CM, McKeone DJ, Buchbinder DK, Katsanis E, Abusin GA, Ahmed I, Law J, Silva JG, Mallhi KK, Burroughs LM, Shah N, Shaw PJ, Greiner R, Shenoy S, Pulsipher MA, Abu-Arja R
Transplant Cell Ther 2022 Jun;28(6):329.e1-329.e9. Epub 2022 Mar 11 doi: 10.1016/j.jtct.2022.03.007. PMID: 35288346
Maisonneuve E, Ben M'Barek I, Leblanc T, Da Costa L, Friszer S, Pernot F, Thomas P, Castaigne V, Toly N'Dour C, Mailloux A, Cortey A, Jouannic JM
Fetal Diagn Ther 2020;47(2):156-164. Epub 2019 Sep 10 doi: 10.1159/000501554. PMID: 31505487
Shalev H, Quider AA, Harosh MB, Kapelushnik J
Pediatr Hematol Oncol 2016 Oct-Nov;33(7-8):457-461. doi: 10.1080/08880018.2016.1247392. PMID: 27960647
Heimpel H, Schwarz K, Ebnöther M, Goede JS, Heydrich D, Kamp T, Plaumann L, Rath B, Roessler J, Schildknecht O, Schmid M, Wuillemin W, Einsiedler B, Leichtle R, Tamary H, Kohne E
Blood 2006 Jan 1;107(1):334-40. Epub 2005 Sep 1 doi: 10.1182/blood-2005-01-0421. PMID: 16141353
Parez N, Dommergues M, Zupan V, Chambost H, Fieschi JB, Delaunay J, Miélot F, Cramer EM, Dommergues JP, Wickramasinghe SN, Tchernia G
Br J Haematol 2000 Aug;110(2):420-3. doi: 10.1046/j.1365-2141.2000.02168.x. PMID: 10971401

Prognosis

Maisonneuve E, Ben M'Barek I, Leblanc T, Da Costa L, Friszer S, Pernot F, Thomas P, Castaigne V, Toly N'Dour C, Mailloux A, Cortey A, Jouannic JM
Fetal Diagn Ther 2020;47(2):156-164. Epub 2019 Sep 10 doi: 10.1159/000501554. PMID: 31505487
Bianchi P, Schwarz K, Högel J, Fermo E, Vercellati C, Grosse R, van Wijk R, van Zwieten R, Barcellini W, Zanella A, Heimpel H
Br J Haematol 2016 Nov;175(4):696-704. Epub 2016 Jul 29 doi: 10.1111/bjh.14271. PMID: 27471141
Heimpel H, Schwarz K, Ebnöther M, Goede JS, Heydrich D, Kamp T, Plaumann L, Rath B, Roessler J, Schildknecht O, Schmid M, Wuillemin W, Einsiedler B, Leichtle R, Tamary H, Kohne E
Blood 2006 Jan 1;107(1):334-40. Epub 2005 Sep 1 doi: 10.1182/blood-2005-01-0421. PMID: 16141353
Wickramasinghe SN, Wood WG
Br J Haematol 2005 Nov;131(4):431-46. doi: 10.1111/j.1365-2141.2005.05757.x. PMID: 16281933
Mori PG, Favareto F, Schenone A, Molinari AC, Boeri E, Massimo L, Bandelloni R, Sansone G
Acta Haematol 1986;75(4):219-23. doi: 10.1159/000206129. PMID: 3096054

Clinical prediction guides

Chrobák L
Acta Medica (Hradec Kralove) 2006;49(3):193-5. PMID: 17117609
Heimpel H, Schwarz K, Ebnöther M, Goede JS, Heydrich D, Kamp T, Plaumann L, Rath B, Roessler J, Schildknecht O, Schmid M, Wuillemin W, Einsiedler B, Leichtle R, Tamary H, Kohne E
Blood 2006 Jan 1;107(1):334-40. Epub 2005 Sep 1 doi: 10.1182/blood-2005-01-0421. PMID: 16141353
Wickramasinghe SN, Wood WG
Br J Haematol 2005 Nov;131(4):431-46. doi: 10.1111/j.1365-2141.2005.05757.x. PMID: 16281933
Zdebska E, Gołaszewska E, Fabijańska-Mitek J, Schachter H, Shalev H, Tamary H, Sandström H, Wahlin A, Kościelak J
Br J Haematol 2001 Sep;114(4):907-13. doi: 10.1046/j.1365-2141.2001.03046.x. PMID: 11564084
Tamary H, Shalmon L, Shalev H, Halil A, Dobrushin D, Ashkenazi N, Zoldan M, Resnitzky P, Korostishevsky M, Bonne-Tamir B, Zaizov R
Am J Hum Genet 1998 May;62(5):1062-9. doi: 10.1086/301834. PMID: 9545404Free PMC Article

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