Kostmann syndrome

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Kostmann syndrome
Classification and external resources
ICD-10 D70
ICD-9 288.01
OMIM 202700 613107 610738 612541 615285 300299
DiseasesDB 29519
eMedicine ped/1260

Kostmann syndrome is a group of diseases that affect myelopoiesis most prominently, causing severe congenital neutropenia (SCN), usually without other prominent overt physical malformations. SCN manifests in infancy with severe infections. Over 90% of SCN responds to treatment with granulocyte colony-stimulating factor (filgrastim), which has significantly improved survival. Kostmann disease, the initial type recognized, was clinically described in 1956. This type, now known as SCN3, is inherited in an autosomal recessive manner, but the commonest subtype of Kostmann syndrome, SCN1, shows autosomal dominant inheritance.

Usage[edit]

Kostmann disease is a form of severe congenital neutropenia (SCN), specifically type 3 (SCN3),[1] which is a rare autosomal recessive condition in which severe chronic neutropenia is detected soon after birth.[2][3] The disorder was discovered in 1956 in an extended family in northern Sweden by Rolf Kostmann, a Swedish doctor.[4][5]

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.[6]

Although mutations of more than 15 genes cause severe congenital neutropenia (in a general sense)[7] 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, Chediak-Higashi syndrome, WHIM syndrome, and glycogen storage disease type Ib.[7] 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. 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.[6]

Presentation[edit]

Infants with SCN have frequent infections: 50% have a significant infection within 1 month, most others by 6 months.[6]

Genetics[edit]

Subtypes of SCN
OMIM Name Gene Chromosome Gene/Locus MIM number
202700 SCN1 ELANE 19p13.3 130130[8]
613107 SCN2 GFI1 1p22.1
610738 SCN3 HAX1 1q21.3
612541 SCN4 G6PC3 17q21.31
615285 SCN5 VPS45 1q21.2
300299 SCNX WASP Xp11.23 300392[9]
Kostmann disease, which is SCN3, is inherited in an autosomal recessive pattern.
The most common form of Kostmann syndrome, SCN1, is autosomal dominant.

Kostmann disease, SCN3, is inherited in an autosomal recessive manner, but the commonest subtype of Kostmann syndrome, SCN1, is autosomal dominant.[2]

A significant proportion of SCN lacks a known mutation.[10] The recognized subtypes of Kostmann syndrome are:

  • SCN1 is the commonest form of SCN, which accounts for 60-80% of SCN,[6] and the first to be genetically typified.[6] This autosomal dominant form that arises from mutations of the ELANE (formerly ELA2) gene on chromosome 19p13.3, which encodes neutrophil elastase.[8] Over a hundred ELANE mutations have been found in SCN1.[11] This same gene is mutated in cyclic neutropenia.[11]
  • SCN2 is caused by heterozygous (autosomal dominant) mutation of the GFI1 gene on chromosome 1p22.[12] GFI1 is a repressor of several transcriptional processes, including ELANE,[6][12] as well as miR-21 and miR-196b micro-RNAs which influence myelopoiesis.[6]
  • SCN3 is the "classical", autosomal recessive form of Kostmann disease which arises from homozygous mutations in the HAX1 gene on chromosome 1p22.1. About one third of SCN3 individuals also have neurological changes including seizures, learning disabilities, or developmental delay.[6]
  • SCN4 is caused by autosomal recessive mutation of the G6PC3 gene on 17q21.[13] SCN4 is associated with structural cardiac abnormalities, enlarged liver, intermittent thrombocytopenia and a prominent superficial venous pattern.[13] A subset of SCN4 has severe primary pulmonary hypertension and respiratory failure.[13]
  • X-linked SCN (SCNX) is caused by mutation in the WASP gene on Xp11.[16]

SCN occasionally may arise from SBDS mutations.[10]

GCSFR abnormalities.[edit]

Diagnosis[edit]

An absolute neutrophil count (ANC) chronically less than 500/mm3, usually less than 200/mm3, is the main sign of Kostmann's. 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 in viral infections, autoimmune neutropenia of infancy, bone marrow suppression from a drug or toxin, hypersplenism, and passive placental transfer of maternal IgG.[6]


A bone marrow test can assist in diagnosis. 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. Neutrophil survival is normal.


Needs mention of (rarer) myelokathexis types. e.g G6PC3 variant and


Pathophysiology[edit]

The various mutations may be responsible for the untimely initiation of apoptosis in myelocytes, producing their premature destruction. 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.

MDS/AML[edit]

Therapy[edit]

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.[17]

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

HSCT[edit]

See also[edit]

References[edit]

[18]

  1. ^ Online 'Mendelian Inheritance in Man' (OMIM) Neutropenia, Severe congenital, 3, Autosomal recessive; SCN3 -610738
  2. ^ a b 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. 
  3. ^ Christensen RD, Calhoun DA (2004). "Congenital neutropenia". Clin Perinatol 31 (1): 29–38. doi:10.1016/j.clp.2004.03.011. PMID 15183654. 
  4. ^ 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. 
  5. ^ 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.  edit
  6. ^ a b c d e f g h i 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. 
  7. ^ a b 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
  8. ^ a b Elastase, neutrophil-expressed; ELANE. Online Mendelian Inheritance in Man. Johns Hopkins University. [1]
  9. ^ WAS gene; WAS. Online Mendelian Inheritance in Man. Johns Hopkins University. [2]
  10. ^ a b 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
  11. ^ a b 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]
  12. ^ a b Neutropenia, Severe Congenital, 2, Autosomal Dominant; SCN2. Online Mendelian Inheritance in Man. Johns Hopkins University. [3]
  13. ^ a b c Neutropenia, Severe Congenital, 4, Autosomal Recessive; SCN4. Online Mendelian Inheritance in Man. Johns Hopkins University. [4]
  14. ^ Neutropenia, Severe Congenital, 5, Autosomal Recessive; SCN5. Online Mendelian Inheritance in Man. Johns Hopkins University. [5]
  15. ^ 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. 
  16. ^ Neutropenia, Severe Congenital, X-linked; SCNX. Online Mendelian Inheritance in Man. Johns Hopkins University. [6]
  17. ^ Hoffbrand AV, Moss PAH, Pettit JE (2005). Essential Haematology. Blackwell Publishing. ISBN 978-1-4051-3649-5. 
  18. ^ Klein, Christoph (2011). "Genetic Defects in Severe Congenital Neutropenia: Emerging Insights into Life and Death of Human Neutrophil Granulocytes". Annual Review of Immunology 29: 399–413. doi:10.1146/annurev-immunol-030409-101259. PMID 21219176. 

External links[edit]