Genetics and Pathophysiology of Severe Congenital Neutropenia Syndromes Unrelated to Neutrophil Elastase

Considerable progress has been made in recent years in understanding of the genetic basis for congenital neutropenia syndromes. With the advent of high-throughput genomic analyzing technologies, the underlying genetic causes of other congenital neutropenia syndromes are expected to be resolved in the near future. This knowledge will provide the foundation for genotype-phenotype correlations for infection susceptibility, response to therapy, and risk of malignant transformation, enabling optimal care for individual patients depending on their molecular pathophysiology. It is hoped that these investigations will enable the development of tailored molecular therapies to specifically correct the aberrant signaling cascades.

Key points

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Considerable progress has been made in recent years in understanding of the genetic basis for congenital neutropenia syndromes.
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With the advent of high-throughput genomic analyzing technologies, the underlying genetic causes of other congenital neutropenia syndromes are expected to be resolved in the near future.
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This knowledge will provide the foundation for genotype-phenotype correlations for infection susceptibility, response to therapy, and risk of malignant transformation, enabling optimal care for individual patients depending on their molecular pathophysiology.
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It is hoped that these investigations will enable the development of tailored molecular therapies to specifically correct the aberrant signaling cascades.

Introduction

Congenital neutropenia represents a heterogeneous group of inherited disorders with the common denominator of persistent and genetically determined paucity of neutrophil granulocytes in the peripheral blood. Neutropenia is termed mild when absolute neutrophil counts (ANCs) range from 1.0 to 1.5 × 10 ⁹/L, moderate with ANCs from 0.5 to 1.0 × 10 ⁹/L, and severe when ANCs are less than 0.5 × 10 ⁹/L.

Congenital neutropenia has to be distinguished from autoimmune neutropenias (usually self-limiting and not causing severe bacterial infections) and benign ethnic neutropenia (prevalent in the Middle East and Africa, not predisposing to infections). By contrast, congenital neutropenia leads to recurrent and severe bacterial (and sometimes fungal) infections. The classic phenotype of autosomal recessive severe congenital neutropenia (SCN) was described by the Swedish pediatrician Rolf Kostmann almost 60 years ago.

In the past, the genetic basis for several mendelian diseases with congenital neutropenia were elucidated and improved understanding of the molecular processes underlying this group of disorders ( Table 1 ). In the United States and Europe, most patients with SCN have either sporadic or autosomal dominance inheritance patterns and bear monoallelic mutations in the neutrophil elastase ( ELANE ) gene (see the article by Horwitz and colleagues elsewhere in this issue for further exploration of this topic). The molecular basis for autosomal recessive SCN is heterogeneous. The classic variant, originally described by Rolf Kostmann, is caused by mutations in the gene encoding for the mitochondrial protein HS1-associated protein (HAX1). In Europe, mutations in HAX1 seem to be more common than in the United States and account for up to 15% to 20% of cases of SCN (European Severe Chronic Neutropenia International Registry, unpublished data). Biallelic mutations in the glucose-6-phosphatase catalytic subunit 3 ( G6PC3 ) gene cause a complex disorder associating congenital neutropenia and various developmental aberrations such as congenital heart defects, urogenital malformations, and facial dysmorphy. Mutations in the GFI1 gene or activating mutations in the Wiskott-Aldrich syndrome ( WAS ) gene represent rare molecular causes of SCN. The relative frequency of these distinct gene defects among patients with SCN differs depending on ethnicity. In particular, in populations with a high degree of consanguinity, autosomal recessive variants of SCN are more prevalent than mutations in ELANE . Despite recent progress in the field, in around one-third of patients with SCN, no pathogenic mutations can be identified.

Table 1

Genetic defects causing congenital neutropenia

Disease	Gene Mutated	Inheritance	Hematopoietic Manifestations	Extrahematopoietic Manifestations	Pathophysiologic Mechanism
(1) SCN
ELANE deficiency (SCN1)	ELANE	AD	CN or CyN	—	Activation of the UPR, excessive apoptosis of myeloid cells
GFI1 deficiency (SCN2)	GFI1	AD	CN, lymphopenia	—	Defective myeloid cell differentiation
HAX1 deficiency (SCN3)	HAX1	AR	CN	Epilepsy, neurologic impairment in some patients	Destabilization of mitochondrial membrane potential, excessive apoptosis of myeloid cells
G6PC3 deficiency (SCN4)	G6PC3	AR	CN, thrombocytopenia	Congenital heart defects, facial dysmorphy, increased visibility of superficial veins, urogenital malformations, failure to thrive, endocrine abnormalities, inner ear hearing loss, hyperelasticity of the skin	Impaired intracellular glucose homeostasis, activation of the UPR, excessive apoptosis of myeloid cells
XLN	WAS	XL	CN, lymphopenia, myelodysplasia	—	Enhanced and discoordinated actin polymerization, defective cytokinesis
(2) Congenital neutropenia: hypopigmentation disorders
Chédiak-Higashi syndrome	LYST / CHS1	AR	CN, defective NK cell function, lysosomal inclusion bodies in leukocytes, macrophage activation syndrome	Oculocutaneous albinism, neurodegeneration	—
Hermansky-Pudlak syndrome, type 2	AP3B1	AR	CN, impaired function of T and NK cells	Oculocutaneous albinism	Defective endosomal function
Griscelli syndrome, type 2	RAB27A	AR	CN, defective cytotoxicity, macrophage activation syndrome	Oculocutaneous albinism	—
P14/ROBLD3/MAPBPIP deficiency	P14 / ROBLD3 / MAPBPIP	AR	CN, defective cytotoxicity, growth failure, lymphoid immunodeficiency	Oculocutaneous albinism	Aberrant distribution of late endosomes
(3) Complex disorders comprising congenital neutropenia
AK2 deficiency	AK2	AR	CN, severe lymphopenia (reticular dysgenesis)	Inner ear hearing loss	Aberrant mitochondrial metabolism caused by lack of adenylate kinase 2
Shwachman-Diamond syndrome	SBDS	AR	CN	Exocrine pancreatic insufficiency, skeletal dysplasia, hepatic and cardiac disease	Mitotic spindle destabilization, genomic instability, enhanced apoptosis
WHIM syndrome	CXCR4	AD	CN, myelokathexis, B cell deficiency	Warts, hypogammaglobulinemia, immunodeficiency	Constitutive activating mutations in CXCR4 associated with myelokathexis and lack of neutrophils in peripheral blood
Poikiloderma with neutropenia	C16ORF57	AR	CN, bone marrow abnormalities	Poikiloderma, increased photosensitivity	Disturbed biogenesis of U6 small nuclear RNA, impaired cell viability
Cartilage-hair hypoplasia	RMRP	AR	CN, immunodeficiency	Hypoplastic hair, skeletal dysplasia	Defective assembly of ribosomes, aberrant cell cycle control and telomere function
CD40L deficiency (HIGM1)	CD40L / CD154	XL	Intermittent CN, combined immunodeficiency including T and B cell deficiency, defective B cell class switch (hyper-IgM syndrome type I)	—	Defective class switch caused by impaired CD40-CD40L interaction, defective T cell priming
Barth syndrome	G4.5 / TAZ	XL	CN (in most patients)	Cardioskeletal myopathy, growth impairment, carnitine deficiency	Mitochondrial dysfunction, excessive apoptosis in myeloid cells
Cohen syndrome	VPS13B / COH	AR	Intermittent CN	Psychomotor retardation, skeletal dysplasia, hypotonia	Suspected function of COH in vesicular transport processes
Pearson syndrome	Deletion of mitochondrial DNA	mtDNA	CN, bone marrow failure	Exocrine pancreas insufficiency, endocrine abnormalities, neuromuscular degeneration	—