Severe Congenital Neutropenia

Severe congenital neutropenia (SCN) affects myelopoiesis and has many different subtypes. SCN manifests in infancy with life-threatening bacterial infections. The treatment proven to be effective is the administration of granulocyte colony-stimulating factor, which elevates the decreased neutrophil count. Kostmann disease (SCN3) has an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritanceinheritance pattern, whereas the most common subtype, SCN1, has autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inheritance.

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Etiology

General facts

In 50%–60% of cases, severe congenital neutropenia (SCN) is due to an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance ELANE gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations. However, the initial mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations described by Kostmann was in HAX1, which is inherited in an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancepattern. X-linked recessive inheritance is due to mutations in the Wiskott-Aldrich syndrome Wiskott-Aldrich syndrome Wiskott-Aldrich syndrome (WAS), also known as eczema-thrombocytopenia-immunodeficiency syndrome, IMD2, or immunodeficiency 2, is a rare genetic mixed disorder of B- and T-cell deficiency that follows an X-linked recessive inheritance pattern. It is caused by a WAS gene mutation that leads to impaired actin cytoskeleton, phagocytosis and chemotaxis, impaired platelet development, and, in general, a loss of humoral and cellular responses. Wiskott-Aldrich Syndrome (WAS) gene protein (WASP).

Subtypes

The following table summarizes each subtype of SCN, the genes involved and their function, as well as their mode of inheritance.

Table: Subtypes of SCN
Type Gene mutated Protein affected Mode of inheritance
SCN1 ELANE (19p13.3) Neutrophil elastase ( mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations leads to misfolded protein, which leads to increased apoptosis) AD
SCN2 GFI1 (1p22.1) Repressor of transcriptional processes ( mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations leads to loss of repression) AD
SCN3 HAX1 (1q21.3) HCLS1-associated protein X-1 (functions in control of apoptosis) AR AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation
SCN4 G6PC3 (17q21.31) G6Pase— mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations leads to abolished enzyme activity, aberrant glycosylation, and enhanced apoptosis of myeloid cells AR AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation
SCN5 VPS45 (1q21.2) Vesicle mediated protein (controls vesicular trafficking) AR AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation
SCNX WAS (Xp11.23)—implicated in Wiskott-Aldrich syndrome Wiskott-Aldrich syndrome Wiskott-Aldrich syndrome (WAS), also known as eczema-thrombocytopenia-immunodeficiency syndrome, IMD2, or immunodeficiency 2, is a rare genetic mixed disorder of B- and T-cell deficiency that follows an X-linked recessive inheritance pattern. It is caused by a WAS gene mutation that leads to impaired actin cytoskeleton, phagocytosis and chemotaxis, impaired platelet development, and, in general, a loss of humoral and cellular responses. Wiskott-Aldrich Syndrome WASP—regulator of actin cytoskeleton Cytoskeleton A cell's cytosol is the liquid inside the cell membrane that surrounds the organelles and cytoskeleton. The cytosol is a complex solution where many biochemical processes take place. The Cell: Cytosol and Cytoskeleton ( mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations is a gain-of-function mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations leading to loss of autoinhibition) X-linked recessive
AD: autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance
AR AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation: autosomal recessive
G6Pase: glucose-6-phosphatase

Classification

Origin of neutropenia

Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia may arise from any of 3 pathogenic pathways:

  • Insufficient bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow production: destruction and infiltration of the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow by infection, malignancy, or drug toxicity
  • Shifts in and increased destruction of neutrophils from the circulating pool of cells
  • Neutrophilic injury may arise from immunologic disorders:
    • Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus
    • Drug toxicities 
    • Splenic sequestration

Types of neutropenia

Hereditary:

  • Congenital neutropenia
  • Inherited and very severe
  • Autosomal dominant inheritance pattern most common
  • More common in infants and young children
  • Chronic neutropenia (Kostmann syndrome):
  • Cyclic neutropenia:
    • Presents in many members of a family
    • Occurs every 3 weeks and continues for 3–6 days per cycle
    • Symptoms: infections, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and ulcer
    • Most children improve after puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty.

Acquired: 

  • More common than hereditary types
  • Immune-mediated neutropenia
  • Drug-induced neutropenia:
    • Drug acts as a hapten inducing antibody formation.
    • Common culprits: 
      • Quinidine 
      • Aminopyrine
      • Penicillin 
      • Cephalosporins Cephalosporins Cephalosporins are a group of bactericidal beta-lactam antibiotics (similar to penicillins) that exert their effects by preventing bacteria from producing their cell walls, ultimately leading to cell death. Cephalosporins are categorized by generation and all drug names begin with "cef-" or "ceph-." Cephalosporins
      • Phenothiazines 
      • Sulfonamides
      • Hydralazine

Autoimmune:

  • Can be primary or secondary
  • Primary form: 
    • Antineutrophil antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins that cause peripheral destruction 
    • Usually mild and self-limited
  • Secondary form:
    • Usually due to another autoimmune disease, infection, or malignancy
    • Very rare in infants and more likely in patients > 1 year of age

Infectious:

  • Viral: 
    • Measles Measles Measles (also known as rubeola) is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae. It is highly contagious and spreads by respiratory droplets or direct-contact transmission from an infected person. Typically a disease of childhood, measles classically starts with cough, coryza, and conjunctivitis, followed by a maculopapular rash. Measles Virus
    • Influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza
    • EBV
    • CMV
    • Viral hepatitides
    • HIV
  • Bacterial/parasitic:
    • Typhoid
    • Toxoplasmosis Toxoplasmosis Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis
    • Brucellosis Brucellosis Brucellosis (also known as undulant fever, Mediterranean fever, or Malta fever) is a zoonotic infection that spreads predominantly through ingestion of unpasteurized dairy products or direct contact with infected animal products. Clinical manifestations include fever, arthralgias, malaise, lymphadenopathy, and hepatosplenomegaly. Brucella/Brucellosis
    • Rickettsial infections
    • Malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Malaria
    • Dengue Dengue Dengue is an infection caused by the Dengue virus (DENV), a small, positive-sense, single-stranded RNA virus of the genus Flavivirus. The majority of infections are asymptomatic. Symptomatic individuals may progress through 3 stages of the disease, with severe manifestations occurring in those with previous infections. Dengue Virus fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever

Mixed: chronic benign neutropenia

  • Rare form
  • Can lead to life-threatening infections
  • More common in children < 4 years of age

Clinical Presentation

Signs and symptoms

  • Recurrent mucosal infections, more so in the mouth, throat, and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, due to low immunity
  • Septicemia
  • Fever and chills
  • Otitis media
  • Stomatitis Stomatitis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis and periodontitis
  • Splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
  • Petechial bleeds and easy bruisability due to depression of other cell lines in most conditions
  • Growth retardation
  • General body malaise
  • Poor appetite and weight loss

Complete history and physical examination

  • Family history is important.
  • Children often present with a history of:
    • Pneumonia
    • Ear infections
    • Tonsillitis Tonsillitis Tonsillitis is inflammation of the pharynx or pharyngeal tonsils, and therefore is also called pharyngitis. An infectious etiology in the setting of tonsillitis is referred to as infectious pharyngitis, which is caused by viruses (most common), bacteria, or fungi. Tonsillitis
    • Gastroenteritis Gastroenteritis Gastroenteritis is inflammation of the stomach and intestines, commonly caused by infections from bacteria, viruses, or parasites. Transmission may be foodborne, fecal-oral, or through animal contact. Common clinical features include abdominal pain, diarrhea, vomiting, fever, and dehydration. Gastroenteritis
    • Skin infections
    • Pharyngitis Pharyngitis Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis
  • On physical examination:
    • Fever (many times there is a fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever without focal signs of disease)
    • Ulcers
    • Gingivitis
    • Abscesses
    • Pneumonia
    • Skin infections
    • Cervical lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
    • Growth retardation

Diagnosis

  • Absolute neutrophil count (ANC):
    • In neutropenia, the ANC is reduced.
    • In infants: ANC < 1000/µL
    • Children > 1 year of age: ANC < 1500/µL (the same definition as an adult)
    • ANC is used to classify neutropenia: 
      • Mild: ANC 1000–1500/µL
      • Moderate: ANC 500–1000/µL
      • Severe: ANC < 500/µL
  • First orders to place:
    • CBC/DIFF: 
      • Will show a low neutrophil count in the peripheral circulation 
      • Aids in calculation of ANC
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones marrow aspiration (BMA) and biopsy:
      • Hypercellular marrow indicates peripheral destruction.
      • Hypocellular marrow indicates bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow infiltration and failure.
  • For clinical concern about infection, order:
    • Cultures (blood, urine, sputum, and wounds)
    • Urinalysis
    • Skin biopsy
    • Stool ova/parasites and cultures
  • Beneficial imaging studies:
    • Radiography of long bones (in cases of congenital neutropenia)
    • Chest X-ray and chest CT if patient has signs of pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
    • Abdominal ultrasonography to evaluate splenomegaly
Calculation of anc with example

How to calculate ANC with example

Image by Lecturio. License: CC BY-NC-SA 4.0

Management

General approach to treatment

  • Remove any offending drugs.
  • Practice good oral hygiene.
  • Use stool softeners (as needed).
  • Perform adequate skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin care.
  • Correct folic acid deficiency (if present).
  • Dietary modifications (including ingestion of properly cooked meats, clean water, and avoidance of acidic foods)

Specific therapies

  • Antibiotics (to address any coexisting infections)
  • Granulocyte colony-stimulating factor administration 
    • Improves neutrophil counts and immune function 
    • Risks: Myelofibrosis and AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
  • Granulocyte transfusion (to replenish any granulocyte deficiencies)
  • IV immunoglobulin (to address any autoimmune component to the neutropenia)
  • Corticosteroids (to lead to overall immunosuppression in cases of autoimmune neutropenia)
Severe congenital neutropenia granulocyte colony stimulating factor

Effects of granulocyte-colony stimulating factor (G-CSF)
Th2: type 2 T helper cell
TREG: T regulatory cells

Image by Lecturio. License: CC BY-NC-SA 4.0

Differential Diagnosis

  • Leukemias, particularly AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia: produce neutropenia through bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow suppression of normal hematopoietic cell lineage due to overproduction of the malignant cell line. Leukemias will often present with markedly elevated WBCs, however, which can be particularly useful in differentiating from neutropenia. Additionally, neutropenia and leukemia are frequently seen in combination due to the side effects of many chemotherapeutic agents. 
  • Aplastic anemia Aplastic Anemia Aplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Aplastic Anemia: result of complete bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow failure to produce hematopoietic cells. Patients with aplastic anemia will demonstrate pancytopenia rather than isolated neutropenia, a helpful differentiation tool between the 2 entities. Aplastic anemia Aplastic Anemia Aplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Aplastic Anemia is frequently a secondary diagnosis , caused by autoimmune syndromes, radiation therapy, chemotherapy, or postviral syndromes. Treatment is complex but can include antithymocyte globulin, cyclosporine, or bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow transplantation, depending on severity, patient age, and previously attempted therapies. 
  • Lymphoma: produces neutropenia using a similar mechanism as the leukemias. If the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow space is overproducing malignant lymphoid cells, there is not enough bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow space to appropriately create the other hematopoietic cell lines. Thus, neutropenia will be seen with a significantly elevated lymphocyte count, which will help differentiate the etiology of neutropenia from other causes. Lymphoma is treated with chemotherapy and commonly includes the R-CHOP—a combination of rituximab, cyclophosphamide, hydroxydaunorubicin, Oncovin (vincristine), and prednisone.

References

  1. Coates, T.D. (2021). Overview of neutropenia in children and adolescents. In Newburger, P., et al. (Ed.), UpToDate. Retrieved May 22, 2021, from https://www.uptodate.com/contents/overview-of-neutropenia-in-children-and-adolescents
  2. Berliner, N. (2020). Approach to the adult with unexplained neutropenia. In Newburger, P., et al. (Ed.), UpToDate. Retrieved May 22, 2021, from https://www.uptodate.com/contents/approach-to-the-adult-with-unexplained-neutropenia
  3. Fischer, A. (2018). Primary immune deficiency diseases. Chapter 344 of Jameson J., et al. (Ed.), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill.

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