Background
Definition: neutropenia and congenital neutropenia
General definition
Congenital neutropenia: an evolving definition
Epidemiology
Clinical description
The consequences of neutropenia: infections
Extra-hematopoietic involvement
Sub group of neutropenia | Disease name/ref | OMIM code | Main hematological features | Extra-hematopoeitic features | Inheritance | Gene localisation | Gene (alias) | Normal function of the gene |
---|---|---|---|---|---|---|---|---|
Congenital Neutropenia without extra hematopoeitic manifestations | 202700 162800 | Severe and permanent Maturation arrest Intermittent/cyclic with variable bone marrow features | No | Dominant | 19q13.3 |
ELANE
| Protease activity Antagonism with alpha 1 antitrypsin | |
Severe congenital neutropenia Somatic mutation of CSF3R | 202700 | Permanent Maturation arrest Unresponsive to GCSF | No | No genetic inheritence | 1p35-p34.3 |
CSF3R
| transmembrane GCSF receptor/intracellular signalling | |
Congenital Neutropenia with innate or adaptive deficiency but no extrahematopoietic features | Severe congenital neutropenia [88] | 202700 | Permanent/severe or mild Sometimes maturation arrest | Internal ear (in mouse model) Lymphopenia | Dominant | 1p22 |
GFI1
| Transcription factor Regulation of oncoprotein |
301000 | Severe permanent Maturation arrest | Monocytopenia | X Linked | Xp11.4-p11.21 |
WAS
| Cytoskeleton homeostasis | ||
WHIM [99] | 193670 | Severe permanent No maturation arrest Myelokathexis | Lymphopenia Thrombocytopenia | Dominant | 2q21 |
CXCR4
| Chemokine receptor (CXCL12) | |
Congenital neutropenia with extra hematopoietic manifestations | 202700 | Maturation arrest | Central nervous system: mental retardation/seizures | Recessive | 1q21.3 |
HAX1
| Anti-apoptotic protein located in mitochondria and in the cytosol | |
Shwachman-Bodian-Diamond disease [65] | 260400 | Mild neutropenia Dysgranulopeosis mild dysmegacacyopoeisis | Exocrine Pancreas deficiency Bone: metaphyseal dysplasia Central nervous system: mental retardation Heart: cardiomyopathy | Recessive | 7q11.22 |
SDBS
| Ribosomal protein Regulation of RNA expression | |
Severe congenital neutropenia [10] | 202700 | Maturation arrest | Skin -prominent superficial venous network Heart: atrial defect Uropathy | Recessive | 17q21 |
G6PC3
| Glucose 6 -phosphatase complex: Catalytic unit | |
Barth disease [77] | 302060 | No maturation arrest | Hypertrophy cardiomyopathy | X Linked | Xq28 |
TAZ (G4.5)
| Tafazzin: Phospholipid membrane homeostasis | |
Hermansky- Pudlak syndrome type 2 [80] | 608233 | No maturation arrest | Albinism | Recessive | 5q14.1 |
AP3B1
| Cargo protein/ER traficking with ELANE interaction | |
Neutropenia with AP14 mutation[78] | No maturation arrest | Albinism | Recessive | 1q21 |
AP14
| Lysosome packaging | ||
604173 | No maturation arrest Minor dysgranulopoetic features | Skin: poikilodermia | Recessive | 16q13 |
16ORF57
| Not known | ||
Glycogen storage type Ib [234] | 232220 | No maturation arrest | hypoglycemia, fasting hyperlactacidemia, and glycogen overload of the liver | Recessive | 11q23.3 |
SLC37A4
| Glucose 6 -phosphatase complex: Trans ER Transporter | |
Cohen syndrome[74] | 216550 | No maturation arrest | psychomotor retardation, clumsiness, microcephaly, characteristic facial features, hypotonia and joint laxity, progressive retinochoroidal dystrophy, myopia | Recessive | 8q22-q23 |
VPS13B
| Sorting and transporting proteins in the ER | |
Diseases not usually assimilated to congenital neutropenia but including chronic neutropenia | IRAK 4 deficiency [95] | 606883 | Permanent mild but severe infection No maturation arrest | No | Recessive | 12q12 |
IRAK4
| Mediators of Toll-like receptor signal transduction |
602378 | No maturation arrest | Axonal neuropathy type Charcot Marie Tooth Eyes: congenital cataract | Dominant | 19p13.2-p12 |
DNM2
| GTPases Regulation of the actin cytoskeleton | ||
Cartilage-hair hypoplasia [125] | 250250 | No maturation arrest | Dwarfism metaphyseal dysplasia Abnormal hair Lymphopenia aganglionic megacolon | Recessive | 9p21-p12 |
RMRP
| Endoribonuclease |
System | Hematological or associated features | Disease | Gene |
---|---|---|---|
Blood/bone marrow maturation | Maturation arrest |
ELANE
HAX 1
WASP
Neutropenia G6PC3
GCSF receptor
|
ELANE
HAX1
WASP
G6PC3
Extra cellular domain of CSF3R
|
No maturation arrest | GSDIB WHIM Shwachman Diamond disease Cohen disease Hermansky Pudlak type 2 |
G6PC T
CXCR4
SBDS
VPS13B
AP3B1
| |
Myelokathexis | WHIM |
CXCR4
| |
Pancreas | External pancreatic insufficiency | Shwachman Diamond disease |
SBDS
|
Eyes | Congenital cataract | Charcot Marie Tooth |
Dynamin 2
|
retinochoroidal dystrophy | Cohen disease |
VPS13B
| |
Heart | Heart: arrythmias | Neutropenia G6PC3 |
G6PC3
|
Dilated Cardiomyopathy | Barth' diseases |
Tafazin
| |
Cardiomyopathy | Shwachman Diamond disease |
SBDS
| |
Various cardiac abnormalities | Shwachman Diamond disease WHIM Neutropenia G6PC3 |
SBDS
CXCR4
G6PC3
| |
Skin | Skin xerosis eczema | Shwachman Diamond disease |
SBDS
|
Skin: prominent superficial veins | Neutropenia G6PC3 |
G6PC3
| |
Skin poikilodermia | SCN with poiikiloderma Type cleruzio |
16ORF57
| |
Skin: Partial or complete albinism | Hermansky Pudlak type 2 AP14 defect Chediak Higashi disease Griscelli disease |
AP3B1
AP14
LYST
RAB27A
| |
Hair: fine, sparse and light-colored | Cartilage Hair hypoplasia |
RMRP
| |
Bone | Metaphyseal dysplasia | Shwachman Diamond disease Cartilage-hair hypoplasia |
SBDS
RMRP
|
Facial Dysmorphia | Cohen disease |
VPS13B
| |
Central nervous system | Mental retardation | Kostmann's disease Shwachman Diamond disease Cohen disease |
Hax 1
SBDS
VPS13B
|
Muscle | Weakness | Neutropenia G6PC3 Axonal Charcot Marie Tooth disease |
G6PC3
Dynamin 2
|
Metabolic pathway | Fasting intolerance and glycogenosis | Glycogen storage disease type Ib |
SLC37A4
|
Inner ear | Inner ear defect | GFI 1/severe chronic neutropenia Reticular dysgenesia |
GFI1
AK2
|
Urogenital tract | Uropathy | Neutropenia G6PC3 |
G6PC3
|
Cryptorchidism | Cohen disease Neutropenia G6PC3 |
VPS13B
G6PC3
|
Physiology of myeloid differentiation
Congenital neutropenia - classification and etiology
Neutropenia with no extra-hematopoietic manifestations and with normal adaptive immunity
ELANE (ELA2): Permanent and cyclic neutropenia
Extracellular G-CSF receptor defects
Congenital neutropenia with extra-hematopoietic manifestations
Kostmann's syndrome and HAX1 mutations
Shwachman-Diamond syndrome
Glucose-6-phosphatase complex disorders: glycogen storage disease type Ib and G6PC3
Neutropenia associated with glycogen storage disease Ib
Neutropenia associated with G6PC3 mutations
Cohen's syndrome
Neutropenia associated with poikilodermia, Clericuzio type
Barth's disease
Neutropenia and albinism: AP14 deficiency
Neutropenia and albinism: Hermansky Pudlak syndrome type 2
Miscellaneous malformative syndromes
Chronic neutropenia with defective naive/adaptive immunity, considered as congenital neutropenia
Neutropenia associated with GFI1 mutations
Permanent congenital neutropenia due to Wiskott-Aldrich syndrome (WAS) gene mutation
Neutropenia associated with IRAK 4 mutations
NK cell deficiency and neutropenia
Wart hypogammaglobulinemia immunodeficiency myelokathexis (WHIM) syndrome
Neutropenia associated with miscellaneous constitutional disorders NOT considered as congenital neutropenia
Chronic neutropenia, with defective innate/adaptive immunity NOT considered as congenital neutropenia
Humoral immune deficiencies
Severe combined immune deficiency and immune deficiency syndromes
Reticular dysgenesis and AK2 gene mutation
22q11 syndrome
Exocytosis disorders
Chediak Higashi syndrome (CHS)
Griscelli syndrome type 2 (GS2)
Familial hemophagocytic lymphohistiocytosis (FHLH)
Other syndromes associated with neutropenia
Blackfan-Diamond anemia
Fanconi anemia and dyskeratosis congenita
Constitutional monosomy 7
Aminoacidopathies
Pearson's syndrome
Cartilage-hair hypoplasia
Chronic neutropenia, recurrent fever, Behçet's disease and amyloidosis
Finnish nephrotic syndrome
Charcot-Marie-Tooth disease and dynamin 2 mutations
Diagnosis of congenital neutropenia
Main category | How to made the diagnosis | Causes in detail (not exhaustive...) |
---|---|---|
Drug related neutropenia
| questioning Safety data | Cytostatic drugs - almost all except asparaginase Anti-infectives penicillins cephalopsorins sulfamids zidovudine acyclovir lévamisole pyrimethamine tranquilisants chlorpromazine phenothiazines anti seizure phenytoin arbamazepine antithyroid drugs propylthiouracil Cardio vascular drug procainamide quinidine Anti rheumatic drugs Gold salts Non steroid ant inflammatory drug colchicine aminopyrine D penicillamine |
Toxic
| Context/questioning | Benzene Ionizing radiation |
Infection
| Germ isolation or serology or any other probes | Typhoid Brucellae gram negative septicemia Mycobacterium Tuberculosis HIV EBV CMV Parvovirus varicela/Zoster A B C hepatitis,. almost all virus Leishmaniasis paludism |
Acquired malignant or benign hemopathy
| Bone marrow smear Bone marrow trephine Bone marrow cytogenetic |
Acute leukemia
Bone marrow metastases
Aplastic idiopathic anemia
Myelodysplasia
Macrophage activation syndrome/hemophagocytic lymphohistiocytosis
|
auto-immunity
| Auto Antibodies/Bone marrow smear - almost normal but sometimes Neutrophil Hemophagocytosis | Primitive or secondary to rhumatoid disease like in Felty syndrome |
Large granular lymphocytosis
| Blood cytology (> 0.4 G/l LGL) Immunophenotype Lymphoid clonality |
Large Lymphocyte Hyperlymphocytosis
|
Endocrinopathy
| Hormonal dosage | Hyper/Hypothyroidy Surrénal deficiency Pan hypopitutarism |
Nutrition deficiency
| Clinical examination Body mass index Vitamin and oligo element dosage | Anorexia nervosia, Marasmus, Copper insufisiency.. |
Idiopathic
| No others cause |