Entry

H00100                      Disease

Name

Neutropenic disorders

Subgroup

Severe congenital neutropenia (SCN)
Nonimmune chronic idiopathic neutropenia of adults (NI-CINA)

Description

Neutropenias represents a series of potentially life-threatening disorders characterised by a reduction in circulating neutrophils. Since neutrophils play a major role in host defense against bacteria, neutropenia patients suffer from frequent episodes of opportunistic bacterial infections. Severe congenital neutropenia (SCN) is a rare neutropenia with a bone marrow maturation arrest of granulocytic differentiation. Kostmann syndrome is an autosomal recessive SCN. The characteristic maturation arrest and the lack of mature neutrophils in peripheral blood of patients with Kostmann syndrome can be explained by the deletion of an anti-apoptotic factor (HAX-1) in myeloid cells of these patients. Heterozygous mutations in the protooncogene growth factor-independent 1 (GFI1) gene are also associated with SCN. In patients with autosomal dominant cyclic neutropenia (CyN), a condition with oscillating neutrophil counts but less severe clinical symptoms, heterozygous mutations in ELA-2/ELANE were discovered. Patients with X-linked severe congenital neutropenia (SCN) have been reported with activating mutations in Wiskott-Aldrich syndrome protein (WASp) leading to a constitutively-active form of the protein, and unregulated actin polymerization.

Category

Primary immunodeficiency

Brite

Human diseases [BR:br08402]
Immune system diseases
  Primary immunodeficiency
   H00100  Neutropenic disorders
Human diseases in ICD-11 classification [BR:br08403]
04 Diseases of the immune system
  Immune system disorders involving white cell lineages
   4B00  Disorders of neutrophil number
    H00100  Neutropenic disorders

Related
pathway

hsa04613

Neutrophil extracellular trap formation

hsa04062

Chemokine signaling pathway

Gene

(SCN1) ELANE [HSA:1991] [KO:K01327]
(SCN2/NI-CINA) GFI1 [HSA:2672] [KO:K09223]
(SCN3) HAX1 [HSA:10456] [KO:K16220]
(SCN4) G6PC3 [HSA:92579] [KO:K01084]
(SCN5) VPS45 [HSA:11311] [KO:K12479]
(SCN6) JAGN1 [HSA:84522] [KO:K25789]
(SCN7) CSF3R [HSA:1441] [KO:K05061]
(SCN8) SRP54 [HSA:6729] [KO:K03106]
(SCN9) CLPB [HSA:81570] [KO:K03695]
(SCNX) WAS [HSA:7454] [KO:K05747]

Drug

Filgrastim [DR:D03235]
Pegfilgrastim [DR:D06889]

Other DBs

ICD-11:

4B00.0

ICD-10:

D70

OMIM:

202700 613107 607847 610738 612541 615285 616022 617014 618752 619813 300299

Reference

PMID:17162365 (SCN1, SCN2, SCNX)

Authors

Kumar A, Teuber SS, Gershwin ME.

Title

Current perspectives on primary immunodeficiency diseases.

Journal

Clin Dev Immunol 13:223-59 (2006)
DOI:10.1080/17402520600800705

Reference

PMID:18424339 (SCN1, SCN2, SCN3, SCN7)

Authors

Morra M, Geigenmuller U, Curran J, Rainville IR, Brennan T, Curtis J, Reichert V, Hovhannisyan H, Majzoub J, Miller DT.

Title

Genetic diagnosis of primary immune deficiencies.

Journal

Immunol Allergy Clin North Am 28:387-412, x (2008)
DOI:10.1016/j.iac.2008.01.004

Reference

PMID:19811314 (SCN1, SCN2, SCN3, SCN4, SCN7)

Authors

Rezaei N, Moazzami K, Aghamohammadi A, Klein C

Title

Neutropenia and primary immunodeficiency diseases.

Journal

Int Rev Immunol 28:335-66 (2009)
DOI:10.1080/08830180902995645

Reference

PMID:19118303 (SCN4)

Authors

Boztug K, Appaswamy G, Ashikov A, Schaffer 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, Bellanne-Chantelot C, Rezaei N, Monkemoller K, Irani-Hakimeh N, Bakker H, Gerardy-Schahn R, Zeidler C, Grimbacher B, Welte K, Klein C

Title

A syndrome with congenital neutropenia and mutations in G6PC3.

Journal

N Engl J Med 360:32-43 (2009)
DOI:10.1056/NEJMoa0805051

Reference

PMID:23738510 (SCN5)

Authors

Vilboux T, Lev A, Malicdan MC, Simon AJ, Jarvinen P, Racek T, Puchalka J, Sood R, Carrington B, Bishop K, Mullikin J, Huizing M, Garty BZ, Eyal E, Wolach B, Gavrieli R, Toren A, Soudack M, Atawneh OM, Babushkin T, Schiby G, Cullinane A, Avivi C, Polak-Charcon S, Barshack I, Amariglio N, Rechavi G, van der Werff ten Bosch J, Anikster Y, Klein C, Gahl WA, Somech R

Title

A congenital neutrophil defect syndrome associated with mutations in VPS45.

Journal

N Engl J Med 369:54-65 (2013)
DOI:10.1056/NEJMoa1301296

Reference

PMID:25129144 (SCN6)

Authors

Boztug K, Jarvinen PM, Salzer E, Racek T, Monch S, Garncarz W, Gertz EM, Schaffer AA, Antonopoulos A, Haslam SM, Schieck L, Puchalka J, Diestelhorst J, Appaswamy G, Lescoeur B, Giambruno R, Bigenzahn JW, Elling U, Pfeifer D, Conde CD, Albert MH, Welte K, Brandes G, Sherkat R, van der Werff Ten Bosch J, Rezaei N, Etzioni A, Bellanne-Chantelot C, Superti-Furga G, Penninger JM, Bennett KL, von Blume J, Dell A, Donadieu J, Klein C

Title

JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia.

Journal

Nat Genet 46:1021-7 (2014)
DOI:10.1038/ng.3069

Reference

PMID:24753537 (SCN7)

Authors

Triot A, Jarvinen PM, Arostegui JI, Murugan D, Kohistani N, Dapena Diaz JL, Racek T, Puchalka J, Gertz EM, Schaffer AA, Kotlarz D, Pfeifer D, Diaz de Heredia Rubio C, Ozdemir MA, Patiroglu T, Karakukcu M, Sanchez de Toledo Codina J, Yague J, Touw IP, Unal E, Klein C

Title

Inherited biallelic CSF3R mutations in severe congenital neutropenia.

Journal

Blood 123:3811-7 (2014)
DOI:10.1182/blood-2013-11-535419

Reference

PMID:28972538 (SCN8)

Authors

Carapito R, Konantz M, Paillard C, Miao Z, Pichot A, Leduc MS, Yang Y, Bergstrom KL, Mahoney DH, Shardy DL, Alsaleh G, Naegely L, Kolmer A, Paul N, Hanauer A, Rolli V, Muller JS, Alghisi E, Sauteur L, Macquin C, Morlon A, Sancho CS, Amati-Bonneau P, Procaccio V, Mosca-Boidron AL, Marle N, Osmani N, Lefebvre O, Goetz JG, Unal S, Akarsu NA, Radosavljevic M, Chenard MP, Rialland F, Grain A, Bene MC, Eveillard M, Vincent M, Guy J, Faivre L, Thauvin-Robinet C, Thevenon J, Myers K, Fleming MD, Shimamura A, Bottollier-Lemallaz E, Westhof E, Lengerke C, Isidor B, Bahram S

Title

Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.

Journal

J Clin Invest 127:4090-4103 (2017)
DOI:10.1172/JCI92876

Reference

PMID:34115842 (SCN9)

Authors

Warren JT, Cupo RR, Wattanasirakul P, Spencer DH, Locke AE, Makaryan V, Bolyard AA, Kelley ML, Kingston NL, Shorter J, Bellanne-Chantelot C, Donadieu J, Dale DC, Link DC

Title

Heterozygous variants of CLPB are a cause of severe congenital neutropenia.

Journal

Blood 139:779-791 (2022)
DOI:10.1182/blood.2021010762

DISEASE: Neutropenic disorders