Severe congenital neutropenia

Last updated
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
Causes Mutation 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 Kostmann 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

References

  1. 1 2 3 4 5 6 Dale DC, Makaryan V (2018) [2002]. "ELANE-Related Neutropenia". GeneReviews . PMID   20301705 . Retrieved 2019-08-12.
  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) 17032: 1–18. doi:10.1038/nrdp.2017.32. hdl:1765/100536. ISSN   2056-676X. PMC   5821468 . PMID   28593997.
  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) 17032: 1–18. doi:10.1038/nrdp.2017.32. hdl:1765/100536. ISSN   2056-676X. PMC   5821468 . PMID   28593997.
  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.

Further reading