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Severe congenital neutropenia
Severe congenital neutropenia is an immunodeficiency characterized by low levels of granulocytes (< 200/mm3) without an associated lymphocyte deficit.
ORPHA:42738Classification level: Group of disorders
- Synonym(s): -
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal dominant or Autosomal recessive or X-linked recessive
- Age of onset: Childhood
- ICD-10: D70
- OMIM: -
- UMLS: C1853118
- MeSH: C537592
- GARD: -
- MedDRA: 10052210
The prevalence in the general population is estimated at 1-1.7/333,300. Annual incidence is around 1/250,000 births.
This neutropenia leads to repeated bacterial or mycotic infections in various locations, mostly cutaneo-mucous, ear, nose, and throat, and pulmonary. Stomatological signs are almost always present after 2 years of age and are distinguished by erosive gingivitis, hemorrhage and pain, associated with papilla on the tongue and mucous membranes. Infections may be very severe or even lethal. Around 15% of patients evolve to acute leukemia or a myelodysplastic syndrome.
To date, mutations in four genes have been implicated in severe congenital neutropenia. These include the neutrophil elastase gene (ELA2), the GFI1 gene, the HAX1 gene and activation genes of Wiskott Aldrich disease (WASP). The combination of these mutations leads to a deficit in the production of neutrophils.
The defining characteristic is cytology showing profound neutropenia associated with monocytosis. An isolated blockage at the promyelocyte stage of the myeloid series associated with eosinophilia and monocytosis is seen on myelogram.
On the discovery of these features a complete biological assessment should be conducted to rule out several differential diagnoses, particularly lymphocytic immune deficiencies and autoimmune neutropenia.
Prenatal diagnosis may be offered if the genotype is known.
The four mutations are transmitted differently: ELA2 and GFI1 are autosomal dominant, HAX1 is autosomal recessive, and WASP is X-linked recessive. Genetic counseling is essential and should take into account family history and the causal mutation.
Management and treatment
All febrile episodes or infections should be reviewed by a hospital and treated actively. Prophylactic antibiotics are used to prevent infections. If this is ineffective, hematopoietic growth factors (G-CSF in particular) can correct both neutropenia and the susceptibility to infections and can be administered either in response to infections or continuously. The dose of G-CSF required varies greatly. Continuous high dose G-CSF (more than 20µg/kg/day) encourages the onset of leukemia in the long term and therefore, in cases requiring continuous high dose treatment, bone marrow transplant should be considered.
The prognosis depends heavily on the quality of care and timeliness of treatment of severe infections, but also on the possibility of a bone marrow transplant, particularly in cases with malignant transformation.
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