Kostmann syndrome
Encyclopedia
Kostmann syndrome, also known as severe congenital neutropenia, autosomal recessive type 3 (SCN3) and Kostmann disease, is a rare autosomal
recessive form of severe chronic
neutropenia
usually detected soon after birth. The disorder was discovered in 1956 by Swedish doctor Kostmann.
one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
Autosomal dominant inheritance indicates that the defective gene responsible for a disorder is located on an autosome
, and only one copy of the gene is sufficient to cause the disorder, when inherited from a parent who has the disorder.
(ANC) chronically less than 500/mm3 is the main sign of Kostmann's. A standard bone marrow
test can give correct diagnosis.
gene are associated with Kostmann disease, i.e. the "classical," autosomal recessive form of severe congenital neutropenia (SCN3).
In patients with the autosomal dominant form of severe congenital neutropenia (SCN1), although the underlying genetic defect in myeloid precursor cells is not entirely elucidated, mutations in the gene (ELA2) encoding neutrophil elastase
appear to be present in most patients. These mutations may be responsible for the untimely initiation of apoptosis in myelocytes, producing their premature destruction, and interrupting the normal cycle of maturation. There may be, in addition, other underlying molecular/genetic changes producing DNA mutations and genome instability, which contribute to initiation and progression of this disease. Regular administration of exogenous granulocyte colony-stimulating factor
(Filgrastim
) clinically improves neutrophil counts and immune function and is the current mainstay of therapy, although this may increase risk for myelofibrosis
and acute myeloid leukemia
in the long term.
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
recessive form of severe chronic
Chronic (medicine)
A chronic disease is a disease or other human health condition that is persistent or long-lasting in nature. The term chronic is usually applied when the course of the disease lasts for more than three months. Common chronic diseases include asthma, cancer, diabetes and HIV/AIDS.In medicine, the...
neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
usually detected soon after birth. The disorder was discovered in 1956 by Swedish doctor Kostmann.
Genetics
Kostmann syndrome is inherited in an autosomal recessive manner, but may occasionally be autosomal dominant. Autosomal recessive inheritance means the defective gene responsible for the disorder is located on an autosome, but two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carryGenetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
Autosomal dominant inheritance indicates that the defective gene responsible for a disorder is located on an autosome
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
, and only one copy of the gene is sufficient to cause the disorder, when inherited from a parent who has the disorder.
Diagnosis
An absolute neutrophil countAbsolute neutrophil count
Absolute neutrophil count is a measure of the number of neutrophil granulocytes present in the blood...
(ANC) chronically less than 500/mm3 is the main sign of Kostmann's. A standard bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
test can give correct diagnosis.
Morphology
Bone marrow usually shows the presence of early granulocytes (promyelocyte/myelocyte arrest) but few maturing forms are seen; neutrophil survival is normal.Pathophysiology
Homozygous mutations in the HAX1HAX1
HCLS1-associated protein X-1 is a protein that in humans is encoded by the HAX1 gene.-Severe congenital neutropenia:Homozygous mutations in HAX1 are associated with autosomal recessive severe congenital neutropenia, also known as Kostmann syndrome....
gene are associated with Kostmann disease, i.e. the "classical," autosomal recessive form of severe congenital neutropenia (SCN3).
In patients with the autosomal dominant form of severe congenital neutropenia (SCN1), although the underlying genetic defect in myeloid precursor cells is not entirely elucidated, mutations in the gene (ELA2) encoding neutrophil elastase
Elastase
In molecular biology, elastase is an enzyme from the class of proteases that break down proteins.- Forms and classification:There exist eight human genes for elastase:Bacterial forms: Organisms such as P...
appear to be present in most patients. These mutations may be responsible for the untimely initiation of apoptosis in myelocytes, producing their premature destruction, and interrupting the normal cycle of maturation. There may be, in addition, other underlying molecular/genetic changes producing DNA mutations and genome instability, which contribute to initiation and progression of this disease. Regular administration of exogenous granulocyte colony-stimulating factor
Granulocyte colony-stimulating factor
Granulocyte colony-stimulating factor is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 ....
(Filgrastim
Filgrastim
Filgrastim is a granulocyte colony-stimulating factor analog used to stimulate the proliferation and differentiation of granulocytes. It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli. ...
) clinically improves neutrophil counts and immune function and is the current mainstay of therapy, although this may increase risk for myelofibrosis
Myelofibrosis
Myelofibrosis, also known as myeloid metaplasia, chronic idiopathic myelofibrosis, osteomyelofibrosis and primary myelofibrosis is a disorder of the bone marrow...
and acute myeloid leukemia
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
in the long term.
External links
- The European network Neutro-Net
- GeneReviews/NCBI/NIH/UW entry on ELANE-Related Neutropenia including Cyclic Neutropenia, Severe Congenital Neutropenia
- Severe Congenital Neutropenia research study of Inherited Bone Marrow Failure Syndromes (IBMFS)
- Medicine Net
- Severe Chronic Neutropenia International Registry