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Kostmann syndrome(SCN3)

MedGen UID:
1713491
Concept ID:
C5235141
Disease or Syndrome
Synonyms: Agranulocytosis infantile; Autosomal recessive severe congenital neutropenia type 3; Kostmann disease; SCN3
SNOMED CT: Severe congenital neutropenia type 3 (770942003); Kostmann syndrome (770942003); Infantile agranulocytosis (770942003); Infantile genetic agranulocytosis (770942003)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): HAX1 (1q21.3)
 
Monarch Initiative: MONDO:0012548
OMIM®: 610738
Orphanet: ORPHA99749

Definition

Severe congenital neutropenia-3 is an autosomal recessive bone marrow failure disorder characterized by low numbers of neutrophils, increased susceptibility to bacterial and fungal infections, and increased risk of developing myelodysplastic syndrome or acute myeloid leukemia. In addition, patients with HAX1 mutations affecting both isoform A and B of the gene develop neurologic abnormalities (summary by Boztug et al., 2010). The Swedish physician Rolf Kostmann (1956) described an autosomal recessive hematologic disorder, termed infantile agranulocytosis, with severe neutropenia with an absolute neutrophil count below 0.5 x 10(9)/l and early onset of severe bacterial infections. The disorder was later termed Kostmann syndrome (Skokowa et al., 2007). Lekstrom-Himes and Gallin (2000) discussed severe congenital neutropenia in a review of immunodeficiencies caused by defects in phagocytes. In addition to Kostmann agranulocytosis, recessively inherited neutropenic syndromes include congenital neutropenia with eosinophilia (257100), Chediak-Higashi syndrome (214500), and Fanconi pancytopenic syndrome (see 227650). For a phenotypic description and a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (202700). [from OMIM]

Clinical features

From HPO
Acute lymphoid leukemia
MedGen UID:
7317
Concept ID:
C0023449
Neoplastic Process
Acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia, is a subtype of acute leukemia, a cancer of the white blood cells. Somatically acquired mutations in several genes have been identified in ALL lymphoblasts, cells in the early stages of differentiation. Germline variation in certain genes may also predispose to susceptibility to ALL (Trevino et al., 2009). Genetic Heterogeneity of Acute Lymphoblastic Leukemia A susceptibility locus for acute lymphoblastic leukemia (ALL1) has been mapped to chromosome 10q21. See also ALL2 (613067), which has been mapped to chromosome 7p12.2; and ALL3 (615545), which is caused by mutation in the PAX5 gene (167414) on chromosome 9p.
Myelodysplasia
MedGen UID:
10231
Concept ID:
C0026985
Congenital Abnormality
Clonal hematopoietic stem cell disorders characterized by dysplasia (ineffective production) in one or more hematopoietic cell lineages, leading to anemia and cytopenia.
Conductive hearing impairment
MedGen UID:
9163
Concept ID:
C0018777
Disease or Syndrome
An abnormality of vibrational conductance of sound to the inner ear leading to impairment of sensory perception of sound.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Clumsiness
MedGen UID:
66690
Concept ID:
C0233844
Sign or Symptom
Lack of physical coordination resulting in an abnormal tendency to drop items or bump into objects.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Impaired vibratory sensation
MedGen UID:
220959
Concept ID:
C1295585
Finding
A decrease in the ability to perceive vibration. Clinically, this is usually tested with a tuning fork which vibrates at 128 Hz and is applied to bony prominences such as the malleoli at the ankles or the metacarpal-phalangeal joints. There is a slow decay of vibration from the tuning fork. The degree of vibratory sense loss can be crudely estimated by counting the number of seconds that the examiner can perceive the vibration longer than the patient.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Recurrent bacterial infections
MedGen UID:
334943
Concept ID:
C1844383
Finding
Increased susceptibility to bacterial infections, as manifested by recurrent episodes of bacterial infection.

Professional guidelines

PubMed

Zeidler C, Boxer L, Dale DC, Freedman MH, Kinsey S, Welte K
Br J Haematol 2000 Jun;109(3):490-5. doi: 10.1046/j.1365-2141.2000.02064.x. PMID: 10886193
Calhoun DA, Christensen RD
Curr Opin Hematol 1998 Jan;5(1):37-41. doi: 10.1097/00062752-199801000-00007. PMID: 9515201

Recent clinical studies

Etiology

Topcuoglu N, Erdem AP, Karacan I, Kulekci G
J Med Microbiol 2019 Apr;68(4):609-615. Epub 2019 Mar 15 doi: 10.1099/jmm.0.000964. PMID: 30875283
Welte K, Zeidler C, Dale DC
Semin Hematol 2006 Jul;43(3):189-95. doi: 10.1053/j.seminhematol.2006.04.004. PMID: 16822461
Carlsson G, Aprikyan AA, Ericson KG, Stein S, Makaryan V, Dale DC, Nordenskjöld M, Fadeel B, Palmblad J, Hentera JI
Haematologica 2006 May;91(5):589-95. PMID: 16670064
Yildirim S, Yapar M, Kubar A
Oral Microbiol Immunol 2006 Apr;21(2):73-8. doi: 10.1111/j.1399-302X.2006.00250.x. PMID: 16476015
Zeidler C, Schwinzer B, Welte K
Rev Clin Exp Hematol 2003 Mar;7(1):72-83. PMID: 14692235

Diagnosis

Han S, Ehrhardt J Jr, Shukla S, Elkbuli A, Nikiforov YE, Gulec SA
Am J Case Rep 2019 Jul 16;20:1027-1034. doi: 10.12659/AJCR.916143. PMID: 31308356Free PMC Article
Roques G, Munzer M, Barthez MA, Beaufils S, Beaupain B, Flood T, Keren B, Bellanné-Chantelot C, Donadieu J
Pediatr Blood Cancer 2014 Jun;61(6):1041-8. Epub 2014 Jan 30 doi: 10.1002/pbc.24964. PMID: 24482108
Zeidler C, Schwinzer B, Welte K
Rev Clin Exp Hematol 2003 Mar;7(1):72-83. PMID: 14692235
Zeidler C, Boxer L, Dale DC, Freedman MH, Kinsey S, Welte K
Br J Haematol 2000 Jun;109(3):490-5. doi: 10.1046/j.1365-2141.2000.02064.x. PMID: 10886193
Calhoun DA, Christensen RD
Curr Opin Hematol 1998 Jan;5(1):37-41. doi: 10.1097/00062752-199801000-00007. PMID: 9515201

Therapy

Roques G, Munzer M, Barthez MA, Beaufils S, Beaupain B, Flood T, Keren B, Bellanné-Chantelot C, Donadieu J
Pediatr Blood Cancer 2014 Jun;61(6):1041-8. Epub 2014 Jan 30 doi: 10.1002/pbc.24964. PMID: 24482108
Welte K, Zeidler C, Dale DC
Semin Hematol 2006 Jul;43(3):189-95. doi: 10.1053/j.seminhematol.2006.04.004. PMID: 16822461
Zeidler C, Schwinzer B, Welte K
Rev Clin Exp Hematol 2003 Mar;7(1):72-83. PMID: 14692235
Zeidler C, Welte K
Semin Hematol 2002 Apr;39(2):82-8. doi: 10.1053/shem.2002.31913. PMID: 11957189
Zeidler C, Boxer L, Dale DC, Freedman MH, Kinsey S, Welte K
Br J Haematol 2000 Jun;109(3):490-5. doi: 10.1046/j.1365-2141.2000.02064.x. PMID: 10886193

Prognosis

Ebihara Y, Manabe A, Tsuruta T, Ishikawa K, Hasegawa D, Ohtsuka Y, Kawasaki H, Ogami K, Wada Y, Kanda T, Tsuji K
Int J Hematol 2007 Dec;86(5):446-50. doi: 10.1007/BF02984003. PMID: 18192114
Welte K, Zeidler C, Dale DC
Semin Hematol 2006 Jul;43(3):189-95. doi: 10.1053/j.seminhematol.2006.04.004. PMID: 16822461
Yildirim S, Yapar M, Kubar A
Oral Microbiol Immunol 2006 Apr;21(2):73-8. doi: 10.1111/j.1399-302X.2006.00250.x. PMID: 16476015
Zeidler C, Schwinzer B, Welte K
Rev Clin Exp Hematol 2003 Mar;7(1):72-83. PMID: 14692235
Zeidler C, Welte K
Semin Hematol 2002 Apr;39(2):82-8. doi: 10.1053/shem.2002.31913. PMID: 11957189

Clinical prediction guides

Kose MD, Canda E, Kağnıcı M, Uçar SK, Onay H, Yıldırım Sozmen E, Karapınar D, Özkınay F, Çoker M
Blood Cells Mol Dis 2019 May;76:1-6. Epub 2018 Aug 10 doi: 10.1016/j.bcmd.2018.07.001. PMID: 30473482
Roques G, Munzer M, Barthez MA, Beaufils S, Beaupain B, Flood T, Keren B, Bellanné-Chantelot C, Donadieu J
Pediatr Blood Cancer 2014 Jun;61(6):1041-8. Epub 2014 Jan 30 doi: 10.1002/pbc.24964. PMID: 24482108
Carlsson G, Aprikyan AA, Tehranchi R, Dale DC, Porwit A, Hellström-Lindberg E, Palmblad J, Henter JI, Fadeel B
Blood 2004 May 1;103(9):3355-61. Epub 2004 Feb 5 doi: 10.1182/blood-2003-04-1011. PMID: 14764541
Defraia E, Marinelli A
J Clin Pediatr Dent 2001 Fall;26(1):99-102. doi: 10.17796/jcpd.26.1.n1vhq267271378l1. PMID: 11688822

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