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Severe congenital neutropenia autosomal dominant(SCN1)

MedGen UID:
348506
Concept ID:
C1859966
Disease or Syndrome
Synonyms: Congenital Neutropenia; ELANE-Related Neutropenia; NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT; SCN1; Severe Congenital Neutropenia
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, 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 heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): ELANE (19p13.3)
OMIM®: 202700

Definition

ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia, both of which are primary hematologic disorders characterized by recurrent fever, skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis), and cervical adenopathy. Infectious complications are generally more severe in congenital neutropenia than in cyclic neutropenia. In congenital neutropenia, omphalitis immediately after birth may be the first sign; in untreated children diarrhea, pneumonia, and deep abscesses in the liver, lungs, and subcutaneous tissues are common in the first year of life. After 15 years with granulocyte colony stimulating factor treatment, the risk of developing myelodysplasia (MDS) or acute myelogenous leukemia AML is approximately 15%-25%. Cyclic neutropenia is usually diagnosed within the first year of life based on approximately three-week intervals of fever and oral ulcerations and regular oscillations of blood cell counts. Cellulitis, especially perianal cellulitis, is common during neutropenic periods. Between neutropenic periods, affected individuals are generally healthy. Symptoms improve in adulthood. Cyclic neutropenia is not associated with risk of malignancy or conversion to leukemia. [from GTR]

Additional descriptions

From GeneReviews
ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia, both of which are primary hematologic disorders characterized by recurrent fever, skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis), and cervical adenopathy. Infectious complications are generally more severe in congenital neutropenia than in cyclic neutropenia. In congenital neutropenia, omphalitis immediately after birth may be the first sign; in untreated children diarrhea, pneumonia, and deep abscesses in the liver, lungs, and subcutaneous tissues are common in the first year of life. After 15 years with granulocyte colony stimulating factor treatment, the risk of developing myelodysplasia (MDS) or acute myelogenous leukemia AML is approximately 15%-25%. Cyclic neutropenia is usually diagnosed within the first year of life based on approximately three-week intervals of fever and oral ulcerations and regular oscillations of blood cell counts. Cellulitis, especially perianal cellulitis, is common during neutropenic periods. Between neutropenic periods, affected individuals are generally healthy. Symptoms improve in adulthood. Cyclic neutropenia is not associated with risk of malignancy or conversion to leukemia.  https://www.ncbi.nlm.nih.gov/books/NBK1533
From OMIM
Severe congenital neutropenia is a heterogeneous disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections (Skokowa et al., 2007). About 60% of affected individuals of European and Middle Eastern ancestry have dominant ELANE mutations, resulting in a form of severe congenital neutropenia, which is designated here as SCN1. Genetic Heterogeneity of Severe Congenital Neutropenia Severe congenital neutropenia is a genetically heterogeneous disorder showing autosomal dominant, autosomal recessive, and X-linked inheritance. Autosomal dominant SCN2 (613107) is caused by mutation in the protooncogene GFI1 (600871) on chromosome 1p22. Autosomal recessive SCN3 (610738) is caused by mutation in the HAX1 gene (605998) on 1q21.3; autosomal recessive SCN4 (612541) is caused by mutation in the G6PC3 gene (611045) on 17q21; autosomal recessive SCN5 (615285) is caused by mutation in the VPS45 gene (610035) on 1q; autosomal recessive SCN6 (616022) is caused by mutation in the JAGN1 gene (616012) on 3p25; and autosomal recessive SCN7 (617014) is caused by mutation in the CSF3R gene (138971) on 1p34. X-linked SCN (SCNX; 300299) is caused by mutation in the WAS gene (300392) on Xp11. For associations pending confirmation, see MOLECULAR GENETICS. See also adult chronic idiopathic nonimmune neutropenia (607847) and chronic benign familial neutropenia (162700). Susceptibility to Myelodysplastic Syndrome/Acute Myeloid Leukemia SCN patients with acquired mutations in the granulocyte colony-stimulating factor receptor (CSF3R; 138971) in hematopoietic cells define a group with high risk for progression to myelodysplastic syndrome and/or acute myeloid leukemia. Approximately 80% of SCN patients who develop AML are heterozygous for somatic CSF3R mutations (summary by Klimiankou et al., 2016).  http://www.omim.org/entry/202700
From GHR
Severe congenital neutropenia is a condition that causes affected individuals to be prone to recurrent infections. People with this condition have a shortage (deficiency) of neutrophils, a type of white blood cell that plays a role in inflammation and in fighting infection. The deficiency of neutrophils, called neutropenia, is apparent at birth or soon afterward. It leads to recurrent infections beginning in infancy, including infections of the sinuses, lungs, and liver. Affected individuals can also develop fevers and inflammation of the gums (gingivitis) and skin. Approximately 40 percent of affected people have decreased bone density (osteopenia) and may develop osteoporosis, a condition that makes bones progressively more brittle and prone to fracture. In people with severe congenital neutropenia, these bone disorders can begin at any time from infancy through adulthood.Approximately 20 percent of people with severe congenital neutropenia develop cancer of the blood-forming tissue (leukemia) or a disease of the blood and bone marrow (myelodysplastic syndrome) during adolescence.Some people with severe congenital neutropenia have additional health problems such as seizures, developmental delay, or heart and genital abnormalities.  https://ghr.nlm.nih.gov/condition/severe-congenital-neutropenia

Clinical features

Acute monocytic leukemia
MedGen UID:
7319
Concept ID:
C0023465
Neoplastic Process
An acute myeloid leukemia in which 80% or more of the leukemic cells are of monocytic lineage including monoblasts, promonocytes, and MONOCYTES.
Growth abnormality
MedGen UID:
808205
Concept ID:
C0262361
Finding
Eosinophilia
MedGen UID:
41824
Concept ID:
C0014457
Disease or Syndrome
Abnormal increase of EOSINOPHILS in the blood, tissues or organs.
Acute monocytic leukemia
MedGen UID:
7319
Concept ID:
C0023465
Neoplastic Process
An acute myeloid leukemia in which 80% or more of the leukemic cells are of monocytic lineage including monoblasts, promonocytes, and MONOCYTES.
Monocytosis
MedGen UID:
39091
Concept ID:
C0085702
Disease or Syndrome
Abnormally high level of monocytes in the blood.
Thrombocytosis
MedGen UID:
163397
Concept ID:
C0836924
Disease or Syndrome
A hematology test result that indicates the presence of higher than normal platelet counts in the peripheral blood.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
A decrease in the number of neutrophils in the peripheral blood.
Severe congenital neutropenia
MedGen UID:
343974
Concept ID:
C1853118
Disease or Syndrome
Severe congenital neutropenia is a condition that causes affected individuals to be prone to recurrent infections. People with this condition have a shortage (deficiency) of neutrophils, a type of white blood cell that plays a role in inflammation and in fighting infection. The deficiency of neutrophils, called neutropenia, is apparent at birth or soon afterward. It leads to recurrent infections beginning in infancy, including infections of the sinuses, lungs, and liver. Affected individuals can also develop fevers and inflammation of the gums (gingivitis) and skin. Approximately 40 percent of affected people have decreased bone density (osteopenia) and may develop osteoporosis, a condition that makes bones progressively more brittle and prone to fracture. In people with severe congenital neutropenia, these bone disorders can begin at any time from infancy through adulthood.Approximately 20 percent of people with severe congenital neutropenia develop cancer of the blood-forming tissue (leukemia) or a disease of the blood and bone marrow (myelodysplastic syndrome) during adolescence.Some people with severe congenital neutropenia have additional health problems such as seizures, developmental delay, or heart and genital abnormalities.
Increased antibody level in blood
MedGen UID:
892675
Concept ID:
C2048011
Laboratory or Test Result
An increased level of gamma globulin (immunoglobulin) in the blood.
Eosinophilia
MedGen UID:
41824
Concept ID:
C0014457
Disease or Syndrome
Abnormal increase of EOSINOPHILS in the blood, tissues or organs.
Acute monocytic leukemia
MedGen UID:
7319
Concept ID:
C0023465
Neoplastic Process
An acute myeloid leukemia in which 80% or more of the leukemic cells are of monocytic lineage including monoblasts, promonocytes, and MONOCYTES.
Monocytosis
MedGen UID:
39091
Concept ID:
C0085702
Disease or Syndrome
Abnormally high level of monocytes in the blood.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
A decrease in the number of neutrophils in the peripheral blood.
Severe congenital neutropenia
MedGen UID:
343974
Concept ID:
C1853118
Disease or Syndrome
Severe congenital neutropenia is a condition that causes affected individuals to be prone to recurrent infections. People with this condition have a shortage (deficiency) of neutrophils, a type of white blood cell that plays a role in inflammation and in fighting infection. The deficiency of neutrophils, called neutropenia, is apparent at birth or soon afterward. It leads to recurrent infections beginning in infancy, including infections of the sinuses, lungs, and liver. Affected individuals can also develop fevers and inflammation of the gums (gingivitis) and skin. Approximately 40 percent of affected people have decreased bone density (osteopenia) and may develop osteoporosis, a condition that makes bones progressively more brittle and prone to fracture. In people with severe congenital neutropenia, these bone disorders can begin at any time from infancy through adulthood.Approximately 20 percent of people with severe congenital neutropenia develop cancer of the blood-forming tissue (leukemia) or a disease of the blood and bone marrow (myelodysplastic syndrome) during adolescence.Some people with severe congenital neutropenia have additional health problems such as seizures, developmental delay, or heart and genital abnormalities.
Increased antibody level in blood
MedGen UID:
892675
Concept ID:
C2048011
Laboratory or Test Result
An increased level of gamma globulin (immunoglobulin) in the blood.
Recurrent bacterial infections
MedGen UID:
893153
Concept ID:
C4020846
Finding
Increased susceptibility to bacterial infections, as manifested by recurrent episodes of bacterial infection.
Increased antibody level in blood
MedGen UID:
892675
Concept ID:
C2048011
Laboratory or Test Result
An increased level of gamma globulin (immunoglobulin) in the blood.

Recent clinical studies

Etiology

Boztug K, Klein C
Curr Opin Immunol 2009 Oct;21(5):472-80. Epub 2009 Sep 24 doi: 10.1016/j.coi.2009.09.003. PMID: 19782549
Zeidler C, Germeshausen M, Klein C, Welte K
Br J Haematol 2009 Feb;144(4):459-67. Epub 2008 Dec 10 doi: 10.1111/j.1365-2141.2008.07425.x. PMID: 19120359
Smith BN, Ancliff PJ, Pizzey A, Khwaja A, Linch DC, Gale RE
Br J Haematol 2009 Mar;144(5):762-70. Epub 2008 Nov 22 doi: 10.1111/j.1365-2141.2008.07493.x. PMID: 19036076
Schäffer AA, Klein C
Curr Opin Allergy Clin Immunol 2007 Dec;7(6):481-94. doi: 10.1097/ACI.0b013e3282f1d690. PMID: 17989524Free PMC Article
Bohn G, Welte K, Klein C
Curr Opin Rheumatol 2007 Nov;19(6):644-50. doi: 10.1097/BOR.0b013e3282f05cc2. PMID: 17917547

Diagnosis

Skokowa J, Dale DC, Touw IP, Zeidler C, Welte K
Nat Rev Dis Primers 2017 Jun 8;3:17032. doi: 10.1038/nrdp.2017.32. PMID: 28593997
Makaryan V, Rosenthal EA, Bolyard AA, Kelley ML, Below JE, Bamshad MJ, Bofferding KM, Smith JD, Buckingham K, Boxer LA, Skokowa J, Welte K, Nickerson DA, Jarvik GP, Dale DC; UW Center for Mendelian Genomics.
Hum Mutat 2014 Jul;35(7):824-7. Epub 2014 May 21 doi: 10.1002/humu.22563. PMID: 24753205Free PMC Article
Malcov M, Reches A, Ben-Yosef D, Cohen T, Amit A, Dgany O, Tamary H, Yaron Y
Prenat Diagn 2010 Mar;30(3):207-11. doi: 10.1002/pd.2437. PMID: 20049848
Welte K, Zeidler C
Hematol Oncol Clin North Am 2009 Apr;23(2):307-20. doi: 10.1016/j.hoc.2009.01.013. PMID: 19327585
Bohn G, Welte K, Klein C
Curr Opin Rheumatol 2007 Nov;19(6):644-50. doi: 10.1097/BOR.0b013e3282f05cc2. PMID: 17917547

Therapy

Skokowa J, Dale DC, Touw IP, Zeidler C, Welte K
Nat Rev Dis Primers 2017 Jun 8;3:17032. doi: 10.1038/nrdp.2017.32. PMID: 28593997
van de Vosse E, Verhard EM, Tool AJ, de Visser AW, Kuijpers TW, Hiemstra PS, van Dissel JT
Ann Hematol 2011 Feb;90(2):151-8. Epub 2010 Aug 28 doi: 10.1007/s00277-010-1056-4. PMID: 20803142Free PMC Article
Zeidler C, Germeshausen M, Klein C, Welte K
Br J Haematol 2009 Feb;144(4):459-67. Epub 2008 Dec 10 doi: 10.1111/j.1365-2141.2008.07425.x. PMID: 19120359
Skokowa J, Germeshausen M, Zeidler C, Welte K
Curr Opin Hematol 2007 Jan;14(1):22-8. PMID: 17133096
Welte K, Zeidler C, Dale DC
Semin Hematol 2006 Jul;43(3):189-95. doi: 10.1053/j.seminhematol.2006.04.004. PMID: 16822461

Prognosis

Skokowa J, Dale DC, Touw IP, Zeidler C, Welte K
Nat Rev Dis Primers 2017 Jun 8;3:17032. doi: 10.1038/nrdp.2017.32. PMID: 28593997
Welte K, Zeidler C, Dale DC
Semin Hematol 2006 Jul;43(3):189-95. doi: 10.1053/j.seminhematol.2006.04.004. PMID: 16822461
Ancliff PJ, Gale RE, Linch DC
Hematology 2003 Jun;8(3):165-71. doi: 10.1080/1024533031000107497. PMID: 12745650
Zeidler C, Welte K
Semin Hematol 2002 Apr;39(2):82-8. PMID: 11957189
Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla MA, Boxer LA, Kannourakis G, Zeidler C, Welte K, Benson KF, Horwitz M
Blood 2000 Oct 1;96(7):2317-22. PMID: 11001877

Clinical prediction guides

Zeidler C, Germeshausen M, Klein C, Welte K
Br J Haematol 2009 Feb;144(4):459-67. Epub 2008 Dec 10 doi: 10.1111/j.1365-2141.2008.07425.x. PMID: 19120359
Skokowa J, Germeshausen M, Zeidler C, Welte K
Curr Opin Hematol 2007 Jan;14(1):22-8. PMID: 17133096
Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla MA, Boxer LA, Kannourakis G, Zeidler C, Welte K, Benson KF, Horwitz M
Blood 2000 Oct 1;96(7):2317-22. PMID: 11001877

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