Severe congenital neutropenia

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Severe congenital neutropenia
Other namesKostmann disease, Kostmann's agranulocytosis, Kostmann's syndrome, congenital agranulocytosis, congenital neutropenia, permanent neutropenia, infantile genetic agranulocytosis, severe infantile genetic neutropenia
Specialty Hematology   OOjs UI icon edit-ltr-progressive.svg
Usual onsetInfancy [1]
TypesSCN1-SCN5, SCNX
CausesMutation in genes, depending on type [1]
Diagnostic method Blood test, genetic testing [1]
Treatment G-CSF, HSCT [1]
Medication Filgrastim [1]
Frequency2-3 in million (2018) [1]

Severe congenital neutropenia (SCN), also often known as Kostmann syndrome or disease, is a group of rare disorders that affect myelopoiesis, causing a congenital form of neutropenia, usually without other physical malformations. SCN manifests in infancy with life-threatening bacterial infections. [2] It causes severe pyogenic infections. It can be caused by autosomal dominant inheritance of the ELANE gene, autosomal recessive inheritance of the HAX1 gene. There is an increased risk of leukemia and myelodysplastic cancers.

Contents

Most cases of SCN respond to treatment with granulocyte colony-stimulating factor (filgrastim), which increases the neutrophil count and decreases the severity and frequency of infections. [2] Although this treatment has significantly improved survival, people with SCN are at risk of long-term complications such as hematopoietic clonal disorders (myelodysplastic syndrome, acute myeloid leukemia).

Kostmann disease (SCN3), the initial subtype recognized, was clinically described in 1956. This type has an autosomal recessive inheritance pattern, whereas the most common subtype, SCN1, shows autosomal dominant inheritance.[ citation needed ]

Presentation

Infants with SCN have frequent infections: 50% have a significant infection within one month, most others by six months. [3] Their etiology is usually bacterial, especially staphylococcal, and they commonly involve abscesses, both cutaneous and of internal organs, pneumonia, mastoiditis (inflammation of the mastoid process), and sepsis. All of these are life-threatening for infants. [4]

Genetics

Subtypes of SCN
OMIM NameGeneChromosomeGene/Locus MIM number
202700 SCN1 ELANE 19p13.3130130 [5]
613107 SCN2 GFI1 1p22.1
610738 SCN3 HAX1 1q21.3
612541 SCN4 G6PC3 17q21.31
615285 SCN5 VPS45 1q21.2
300299 SCNX WASP Xp11.23300392 [6]
The most common form, SCN1, is autosomal dominant. Autosomal dominant - en.svg
The most common form, SCN1, is autosomal dominant.
Kostmann disease, which is SCN3, is inherited in an autosomal recessive pattern. Autosomal recessive - en.svg
Kostmann disease, which is SCN3, is inherited in an autosomal recessive pattern.

Kostmann disease, SCN3, is inherited in an autosomal recessive manner, but the commonest subtype of Kostmann syndrome, SCN1, is autosomal dominant. [7]

A significant proportion of SCN lacks a known mutation. [8] The recognized subtypes of Kostmann syndrome are:

SCN occasionally may arise from SBDS mutations. [8]

Usage

Severe congenital neutropenia (SCN) is used as the overarching term for all diseases that affect myelopoiesis most prominently. Kostmann syndrome can restrictively refer to Kostmann disease specifically, or can be used synonymously with SCN as an umbrella term. These syndrome subtypes are phenotypically similar despite arising from different gene abnormalities. [3]

Kostmann disease is a form of severe congenital neutropenia (SCN), specifically type 3 (SCN3), [15] which is a rare autosomal recessive condition in which severe chronic neutropenia is detected soon after birth. [7] [16] The disorder was discovered in 1956 in an extended family in northern Sweden by Rolf Kostmann, a Swedish doctor. [17] [18]

Although mutations of more than 15 genes cause severe congenital neutropenia (in a general sense) [19] not all of these are usually considered as SCN. Clinical usage excludes two broad categories of congenital neutropenia. Diseases are excluded that overtly affect multiple systems rather than impacting myelopoiesis most prominently. Thus SCN excludes the severe neutropenia which can occur in congenital diseases such as Shwachman–Diamond syndrome, Barth syndrome, Chédiak–Higashi syndrome, WHIM syndrome, and glycogen storage disease type Ib. [19] A further group of other miscellaneous inherited disorders, such as hyper IgM syndrome, Hermansky–Pudlak syndrome (HPS), Griscelli syndrome (GS), PN, P14 deficiency, Cohen syndrome, Charcot–Marie–Tooth disease (CMT) can show congenital neutropenia, but lack bone marrow findings typical of SCN.[ citation needed ]

This group of diseases may also have additional features such as partial albinism, retinopathy, or neuropathy, and are not inclined to degenerate into acute myelogenous leukemia. [3]

GATA2 deficiency

GATA2 deficiency is a grouping of several disorders caused by common defect, viz., familial or sporadic inactivating mutations in one of the two parental GATA2 genes. These autosomal dominant mutations cause a reduction, i.e. a haploinsufficiency, in the cellular levels of the gene's product, GATA2. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lympathic-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are deficient and individuals develop over time hematological, immunological, lymphatic, or other presentations that may begin as apparently benign abnormalities but commonly progress to a more serious disorder. A small but significant percentage of individuals with GATA2 deficiency's present with congenital neutropenia. This neutropenia is typically mild, often persists for years, and therefore is not a Kostmann syndrome disorder. Over time, however, the deficiency commonly progresses to include thrombocytopenia, increases susceptibility to infections due to, e.g. atypical mycobacteria or human papillomavirus, dysfunction of non-hematological organs, the myelodysplastic syndrome, and/or a leukemia, particularly acute myelogenous leukemia. [20] [21] [22]

Pathophysiology

The various mutations are responsible for the untimely initiation of apoptosis in myelocytes, usually at the promyelocyte stage, leading to their premature destruction or maturation arrest in the bone marrow. [23] The ineffective production of neutrophils leads to a decrease in the absolute neutrophil count and a subsequent increased susceptibility to infections. 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.[ citation needed ]

Diagnosis

The diagnosis of severe congenital neutropenia| involves a systematic approach that includes careful clinical examination, such as blood tests and genetic testing, to confirm neutrophil deficiency. [24] This includes checking for specific genetic mutations associated with SCN. Patients with SCN will often exhibit recurrent, severe infections due to consistently low neutrophil counts. [25] [26] Initial diagnostic steps typically include a complete blood count (CBC) to assess the actual neutrophil levels of a patient. [27] Absolute neutrophil count (ANC) chronically less than 500/mm3, usually less than 200/mm3, is the main sign of SCN. Other elements include the severity of neutropenia, the chronology (from birth; not emerging later), and other normal findings (hemoglobin, platelets, general body health). [26] Other elements include the severity of neutropenia, the chronology (from birth; not emerging later), and other normal findings (hemoglobin, platelets, general body health). Isolated neutropenia in infants can occur due to viral infections, autoimmune neutropenia of infancy, bone marrow suppression from a drug or toxin, hypersplenism, and passive placental transfer of maternal IgG. [24]

A Bone marrow biopsy is also recommended to evaluate bone marrow function to remove concerns or rule out other possible hematologic disorders. [28] The bone marrow usually shows early granulocyte precursors, but myelopoietic development stops ("arrests") at the promyelocyte and/or myelocyte stage, so that few maturing forms are seen. [29] Genetic testing is then performed to detect mutations in genes that have been found to be commonly linked to SCN; this includes genes such as ELANE, HAX1, G6PC3, and GF1, which are critical for the proper development of neutrophils as well as the production and function of these hematopoietic cells. [30] [31] Genetic testing is essential to distinguish SCN from other neutropenia disorders. Genetic analysis also provides information on inheritance patterns, as SCN can be inherited in either autosomal dominant, autosomal recessive, or, in very rare cases, X-linked inheritance. [28] These comprehensive diagnostic processes permit precise classification of SCN based on genetic, symptomatic, and clinical analysis, leading to treatment specific to SCN. [28]

Treatment

Regular administration of exogenous granulocyte colony-stimulating factor (filgrastim) clinically improves neutrophil counts and immune function and is the mainstay of therapy, although this may increase risk for myelofibrosis and acute myeloid leukemia in the long term. [32]

Over 90% of SCN responds to treatment with granulocyte colony-stimulating factor (filgrastim), which has significantly improved survival.[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Genetic disorder</span> Health problem caused by one or more abnormalities in the genome

A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.

<span class="mw-page-title-main">Neutropenia</span> Abnormally low concentration of neutrophils (a type of white blood cell) in the blood

Neutropenia is an abnormally low concentration of neutrophils in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria, bacterial fragments and immunoglobulin-bound viruses in the blood. People with neutropenia are more susceptible to bacterial infections and, without prompt medical attention, the condition may become life-threatening.

Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition. Immunocompromisation may also be due to genetic diseases/flaws such as SCID.

Myelokathexis is a congenital disorder of the white blood cells that causes severe, chronic leukopenia and neutropenia. The disorder is believed to be inherited in an autosomal dominant manner. Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo). The disorder shows prominent neutrophil morphologic abnormalities.

<span class="mw-page-title-main">Cyclic neutropenia</span> Medical condition

Cyclic neutropenia (CyN) is a rare hematologic disorder and form of congenital neutropenia that tends to occur approximately every three weeks and lasting for few days at a time due to changing rates of neutrophil production by the bone marrow. It causes a temporary condition with a low absolute neutrophil count and because the neutrophils make up the majority of circulating white blood cells it places the body at severe risk of inflammation and infection. In comparison to severe congenital neutropenia, it responds well to treatment with granulocyte colony-stimulating factor (filgrastim), which increases the neutrophil count, shortens the cycle length, as well decreases the severity and frequency of infections.

<span class="mw-page-title-main">Nijmegen breakage syndrome</span> Medical condition

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive congenital disorder causing chromosomal instability, probably as a result of a defect in the double Holliday junction DNA repair mechanism and/or the synthesis dependent strand annealing mechanism for repairing double strand breaks in DNA.

<span class="mw-page-title-main">Hyperimmunoglobulin E syndrome</span> Medical condition

Hyperimmunoglobulinemia E syndrome (HIES), of which the autosomal dominant form is called Job's syndrome or Buckley syndrome, is a heterogeneous group of immune disorders. Job's is also very rare at about 300 cases currently in the literature.

<span class="mw-page-title-main">GATA1</span> Protein-coding gene in humans

GATA-binding factor 1 or GATA-1 is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species.

<span class="mw-page-title-main">Neutrophil elastase</span> Protein-coding gene in the species Homo sapiens

Neutrophil elastase is a serine proteinase in the same family as chymotrypsin and has broad substrate specificity. Neutrophil elastase is secreted by neutrophils during inflammation, and destroys bacteria and host tissue. It also localizes to neutrophil extracellular traps (NETs), via its high affinity for DNA, an unusual property for serine proteases.

<span class="mw-page-title-main">Purine nucleoside phosphorylase deficiency</span> Medical condition

Purine nucleoside phosphorylase deficiency is a rare autosomal recessive metabolic disorder which results in immunodeficiency.

Congenital hypoplastic anemia is a congenital disorder that occasionally also includes leukopenia and thrombocytopenia and is characterized by deficiencies of red cell precursors.

<span class="mw-page-title-main">Shwachman–Diamond syndrome</span> Medical condition

Shwachman–Diamond syndrome (SDS), or Shwachman–Bodian–Diamond syndrome, is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal and cardiac abnormalities and short stature. After cystic fibrosis (CF), it is the second most common cause of exocrine pancreatic insufficiency in children. It is associated with the SBDS gene and has autosomal recessive inheritance.

<span class="mw-page-title-main">G6PC3</span> Protein-coding gene in the species Homo sapiens

Glucose-6-phosphatase 3, also known as glucose-6-phosphatase beta, is an enzyme that in humans is encoded by the G6PC3 gene.

MonoMAC syndrome is a rare autosomal dominant syndrome associated with: monocytopenia, B and NK cell lymphopenia; mycobacterial, viral, fungal, and bacterial opportunistic infections; and virus infection-induced cancers. The disorder often progresses to the development of myelodysplasia, myeloid leukemias, and other types of cancer. MonoMAC is a life-threatening and precancerous disorder.

<span class="mw-page-title-main">Reticular dysgenesis</span> Medical condition

Reticular dysgenesis (RD) is a rare, inherited autosomal recessive disease that results in immunodeficiency. Individuals with RD have mutations in both copies of the AK2 gene. Mutations in this gene lead to absence of AK2 protein. AK2 protein allows hematopoietic stem cells to differentiate and proliferate. Hematopoietic stem cells give rise to blood cells.

Neutrophil-specific granule deficiency is a rare congenital immunodeficiency characterized by an increased risk for pyogenic infections due to defective production of specific granules and gelatinase granules in patient neutrophils.

GATA2 deficiency is a grouping of several disorders caused by common defect, namely, familial or sporadic inactivating mutations in one of the two parental GATA2 genes. Being the gene haploinsufficient, mutations that cause a reduction in the cellular levels of the gene's product, GATA2, are autosomal dominant. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lymphatic-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are deficient and individuals develop over time hematological, immunological, lymphatic, or other presentations that may begin as apparently benign abnormalities but commonly progress to severe organ failure, opportunistic infections, virus infection-induced cancers, the myelodysplastic syndrome, and/or leukemia. GATA2 deficiency is a life-threatening and precancerous condition.

P14 deficiency is a rare autosomal recessive disease characterized as a primary immunodeficiency syndrome. This disease was first identified within a white Mennonite family by Professor Bodo Grimbacher and Professor Christoph Klein's teams in 2006. Four out of 15 offspring in this family showed symptoms including short stature, recurrent infection of Streptococcus pneumoniae, and dysfunction of cells that contain specific lysosome-related organelles, including cytotoxic T cells, melanocytes, and neutrophil granulocytes.

References

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  2. 1 2 Boztug, K; Appaswamy, G; Ashikov, A; Schäffer, AA; Salzer, U; Diestelhorst, J; Germeshausen, M; Brandes, G; Lee-Gossler, J; Noyan, F; Gatzke, AK; Minkov, M; Greil, J; Kratz, C; Petropoulou, T; Pellier, I; Bellanné-Chantelot, C; Rezaei, N; Mönkemöller, K; Irani-Hakimeh, N; Bakker, H; Gerardy-Schahn, R; Zeidler, C; Grimbacher, B; Welte, K; Klein, C (1 January 2009). "A syndrome with congenital neutropenia and mutations in G6PC3". The New England Journal of Medicine. 360 (1): 32–43. doi:10.1056/nejmoa0805051. PMC   2778311 . PMID   19118303.
  3. 1 2 3 4 5 6 7 8 Hoffman, R; Benz, EJ; Silberstein, LE; Heslop, H; Weitz J; Anastasi, J. (2012). Hematology: Basic Principles and Practice (6th ed.). Elsevier. ISBN   978-1-4377-2928-3.
  4. ↑ Kawalec, Wanda (2015). Pediatria. Warsaw: PZWL. p. 1070. ISBN   978-83-200-4631-1.
  5. 1 2 Elastase, neutrophil-expressed; ELANE. Online Mendelian Inheritance in Man. Johns Hopkins University.
  6. ↑ WAS gene; WAS. Online Mendelian Inheritance in Man. Johns Hopkins University.
  7. 1 2 Zeidler C, Welte K (2002). "Kostmann syndrome and severe congenital neutropenia". Semin. Hematol. 39 (2): 82–8. doi:10.1053/shem.2002.31913. PMID   11957189.
  8. 1 2 Xia J, Bolyard AA, Rodger E et al. Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia. Br J Haematol. 2009;147(4):535. PMID|19775295
  9. 1 2 Germeshausen, M., Deerberg, S., Peter, Y., et al. The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia. Hum. Mutat. 34: 905-914, 2013. PMID|23463630]
  10. 1 2 Neutropenia, Severe Congenital, 2, Autosomal Dominant; SCN2. Online Mendelian Inheritance in Man. Johns Hopkins University.
  11. 1 2 3 Neutropenia, Severe Congenital, 4, Autosomal Recessive; SCN4. Online Mendelian Inheritance in Man. Johns Hopkins University.
  12. ↑ Neutropenia, Severe Congenital, 5, Autosomal Recessive; SCN5. Online Mendelian Inheritance in Man. Johns Hopkins University.
  13. ↑ Stepensky P, Saada A, Cowan M, et al. (June 2013). "The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy". Blood. 121 (25): 5078–87. doi: 10.1182/blood-2012-12-475566 . PMID   23599270.
  14. ↑ Neutropenia, Severe Congenital, X-linked; SCNX. Online Mendelian Inheritance in Man. Johns Hopkins University.
  15. ↑ Online Mendelian Inheritance in Man (OMIM): Neutropenia, Severe congenital, 3, Autosomal recessive; SCN3 - 610738
  16. ↑ Christensen RD, Calhoun DA (2004). "Congenital neutropenia". Clin Perinatol. 31 (1): 29–38. doi:10.1016/j.clp.2004.03.011. PMID   15183654.
  17. ↑ Kostmann R (1956). "Infantile genetic agranulocytosis; agranulocytosis infantilis hereditaria". Acta Paediatr. 45 (Suppl 105): 1–78. doi:10.1111/j.1651-2227.1956.tb06875.x. PMID   13326376. S2CID   71420679.
  18. ↑ Klein, C.; Grudzien, M.; Appaswamy, G.; Germeshausen, M.; Sandrock, I.; Schäffer, A. A.; Rathinam, C.; Boztug, K.; Schwinzer, B.; Rezaei, N.; Bohn, G.; Melin, M.; Carlsson, G. R.; Fadeel, B.; Dahl, N.; Palmblad, J.; Henter, J. I.; Zeidler, C.; Grimbacher, B.; Welte, K. (Jan 2006). "HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease)". Nature Genetics. 39 (1): 86–92. doi:10.1038/ng1940. PMID   17187068. S2CID   22757727.
  19. 1 2 McDermott DH, De Ravin SS, Jun HS et al. Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis. Blood. 2010;116(15):2793. PMID|20616219
  20. ↑ Mir MA, Kochuparambil ST, Abraham RS, Rodriguez V, Howard M, Hsu AP, Jackson AE, Holland SM, Patnaik MM (April 2015). "Spectrum of myeloid neoplasms and immune deficiency associated with germline GATA2 mutations". Cancer Medicine. 4 (4): 490–9. doi:10.1002/cam4.384. PMC   4402062 . PMID   25619630.
  21. ↑ Crispino JD, Horwitz MS (April 2017). "GATA factor mutations in hematologic disease". Blood. 129 (15): 2103–2110. doi:10.1182/blood-2016-09-687889. PMC   5391620 . PMID   28179280.
  22. ↑ Hirabayashi S, Wlodarski MW, Kozyra E, Niemeyer CM (August 2017). "Heterogeneity of GATA2-related myeloid neoplasms". International Journal of Hematology. 106 (2): 175–182. doi: 10.1007/s12185-017-2285-2 . PMID   28643018.
  23. ↑ Newburger, Peter E.; Dale, David C. (July 2013). "Evaluation and Management of Patients With Isolated Neutropenia". Seminars in Hematology. 50 (3): 198–206. doi:10.1053/j.seminhematol.2013.06.010. PMC   3748385 . PMID   23953336.
  24. 1 2 Hoffman, R; Benz, EJ; Silberstein, LE; Heslop, H; Weitz J; Anastasi, J. (2012). Hematology: Basic Principles and Practice (6th ed.). Elsevier. ISBN   978-1-4377-2928-3.
  25. ↑ Skokowa, Julia; Dale, David C.; Touw, Ivo P.; Zeidler, Cornelia; Welte, Karl (2017-06-08). "Severe congenital neutropenias". Nature Reviews Disease Primers. 3 (1): 1–18. doi:10.1038/nrdp.2017.32. ISSN   2056-676X.
  26. 1 2 "Congenital Neutropenia Syndromes | NIAID: National Institute of Allergy and Infectious Diseases". www.niaid.nih.gov. 2019-04-01. Retrieved 2024-11-13.
  27. ↑ "Severe Congenital Neutropenia | Symptoms, Diagnosis & Treatment". www.cincinnatichildrens.org. Retrieved 2024-11-13.
  28. 1 2 3 "Congenital Neutropenia Syndromes | NIAID: National Institute of Allergy and Infectious Diseases". www.niaid.nih.gov. 2019-04-01. Retrieved 2024-11-13.
  29. ↑ Hoffman, R; Benz, EJ; Silberstein, LE; Heslop, H; Weitz J; Anastasi, J. (2012). Hematology: Basic Principles and Practice (6th ed.). Elsevier. ISBN   978-1-4377-2928-3.
  30. ↑ Skokowa, Julia; Dale, David C.; Touw, Ivo P.; Zeidler, Cornelia; Welte, Karl (2017-06-08). "Severe congenital neutropenias". Nature Reviews Disease Primers. 3 (1): 1–18. doi:10.1038/nrdp.2017.32. ISSN   2056-676X.
  31. ↑ "Severe Congenital Neutropenia | Symptoms, Diagnosis & Treatment". www.cincinnatichildrens.org. Retrieved 2024-11-13.
  32. ↑ Hoffbrand AV, Moss PA, Pettit JE (2005). Essential Haematology. Blackwell Publishing. ISBN   978-1-4051-3649-5.

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