severe congenital neutropenia

Severe Congenital Neutropenia (SCN): A Rare and Serious Condition

Severe congenital neutropenia, also known as Kostmann syndrome or disease, is a rare group of inherited disorders that affect the production of neutrophils, a type of white blood cell crucial for fighting infections. [1][2]

Characteristics and Risks

Individuals with SCN have low levels of neutrophils (less than 200/mm^3) without an associated lymphocyte deficit, making them more susceptible to repeated infections. [5] This condition increases the risk of developing myelodysplastic syndromes (MDS) and leukemia due to impaired maturation of neutrophil granulocytes. [6][9]

Causes and Inheritance

SCN is a rare inherited disorder, with various genetic mutations contributing to its development. The exact cause of SCN can vary depending on the specific mutation or syndrome involved. [3][4][8]

Symptoms and Diagnosis

The symptoms of SCN may include recurrent infections, fever, and fatigue. A diagnosis is typically made through blood tests that reveal low neutrophil counts and bone marrow examination to assess maturation and production of neutrophils. [2][7]

Treatment and Management

While there is no cure for SCN, treatment options focus on managing symptoms and preventing infections. This may involve antibiotics, antifungal medications, and supportive care to address complications arising from the condition. [1][5]

Severe congenital neutropenia, also known as Kostmann syndrome, is a rare genetic disorder characterized by an extremely low count of neutrophils, a type of white blood cell that plays a crucial role in fighting infections.

Common signs and symptoms:

• Recurring fevers [3]
• Mouth sores (ulcers) [7]
• Inflammation of the tissues surrounding the mouth and gums (gingivitis) [7]
• Increased risk of life-threatening infections, particularly in the first months of life [6]
• Oral ulcers [7]
• Gingivitis that may lead to early loss of permanent teeth [7]

Additional symptoms:

• Seizures, developmental delay, or heart and genital abnormalities in some cases [1]
• Abscesses (or boils) on the skin, oral infections, and pneumonia due to recurrent infections [4]
• Sore throat, cough or shortness of breath, nasal congestion, diarrhea or loose bowels, and burning during urination [5]

Increased risk:

• Severe congenital neutropenia increases the risk of repeated infections in affected individuals [8]
• Low levels of granulocytes (< 200/mm3) without an associated lymphocyte deficit [9]

Severe congenital neutropenia (SCN) is a rare genetic disorder characterized by abnormally low levels of neutrophils, a type of white blood cell that plays a crucial role in fighting infections.

Diagnostic tests for SCN:

• Bone marrow biopsy: This test can be very helpful in diagnosing severe congenital neutropenia. Bone marrow examination can rule out malignant conditions and provide information on the presence of neutrophil precursors.
• Targeted sequence testing: This genetic test is used to detect mutations in specific genes, such as ELANE and HAX1, which are associated with SCN. It can help confirm a diagnosis of SCN by identifying the underlying genetic cause.
• Next-generation sequencing (NGS): NGS is a comprehensive genetic test that can detect single nucleotide and copy number variants in multiple genes associated with SCN. This test is useful for detecting germline variants in 35 genes known to cause SCN.
• Complete Blood Count (CBC): A CBC, also known as a Full Blood Count (FBC), measures the levels of various white blood cells, including neutrophils. This test can help identify deficiencies and is often used as an initial screening tool for SCN.

Genetic sequencing: Genetic sequencing is a crucial diagnostic tool for SCN. Sequencing ELANE should be considered first, as mutations in this gene are associated with SCN [5]. Additionally, clinical testing is available for mutations in the following three SCN-related genes: ELA2, HAX1, and G6PC3 [8].

These diagnostic tests can help confirm a diagnosis of SCN and provide valuable information on the underlying genetic cause. Early diagnosis and treatment are essential for managing SCN and preventing complications.

References:

[1] Targeted sequence testing is offered for the detection of mutations in the ELANE and HAX1 genes, which can help confirm a diagnosis of congenital or cyclic neutropenia [1].

[2] Bone marrow biopsy can be very helpful in the diagnosis of severe congenital neutropenia [2].

[3] This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 30 genes associated with severe congenital neutropenia [3].

[4] This panel is designed for detection of germline variants in 35 genes known to cause severe congenital neutropenia (SCN), including cyclic neutropenia, [4].

[5] When using genetic sequencing to confirm a diagnosis of severe congenital neutropenia, sequencing ELANE should be considered first, as mutations in this gene are associated with SCN [5].

[8] Clinical testing is currently available in our laboratory for mutations in the following three SCN-related genes: ELA2, HAX1, and G6PC3 [8].

Treatment Options for Severe Congenital Neutropenia

Severe congenital neutropenia (SCN) is a rare and serious condition characterized by an extremely low count of neutrophils, a type of white blood cell that plays a crucial role in fighting infections. The treatment of SCN focuses on managing the symptoms and preventing recurrent infections.

• Granulocyte Colony-Stimulating Factor (G-CSF): Daily subcutaneous administration of G-CSF is considered the treatment of choice for SCN, as it leads to a substantial increase in blood neutrophil count, reduction of infection risk, and improvement in quality of life [5][8].
• Antibiotics: Aggressive intravenous parenteral antibiosis with a combination of a third-generation cephalosporin and an aminoglycoside should be considered for the treatment of infections in SCN patients [3].
• Bone Marrow Transplantation: In some cases, bone marrow transplantation may be necessary to replace the defective bone marrow with healthy stem cells.
• Supportive Care: Supportive care, including antimicrobial prophylaxis and management of complications, is essential in the treatment of SCN.

Preventing Recurrent Infections

To prevent recurrent infections, it is essential to maintain an adequate neutrophil count through G-CSF therapy. Additionally, antimicrobial prophylaxis may be useful in preventing recurrent infections [1].

References:

[1] Dec 20, 2022 — Antimicrobial prophylaxis may be useful in preventing recurrent infections.

[3] Dec 20, 2022 — Aggressive intravenous parenteral antibiosis with a combination of a third-generation cephalosporin and an aminoglycoside should be considered.

[5] by J Skokowa · 2017 · Cited by 365 — Daily subcutaneous G-CSF administration is the treatment of choice and leads to a substantial increase in blood neutrophils count, reduction of ...

[8] Jan 17, 2019 — The mainstay of care is supportive treatment with granulocyte colony-stimulating factor (G-CSF) titrated to maintain an ANC (absolute neutrophil ...

Severe congenital neutropenia, also known as Kostmann syndrome, is a rare genetic disorder characterized by low levels of granulocytes in the blood. When diagnosing this condition, it's essential to consider differential diagnoses that can present with similar symptoms.

Possible Differential Diagnoses:

• Cystic fibrosis: This genetic disorder can cause severe neutropenia, among other symptoms.
• Pearson syndrome: A rare genetic disorder characterized by cytologic abnormalities and neutropenia.
• Severe combined immunodeficiency (SCID): A group of disorders that impair the immune system's ability to fight infections.
• Leukemia: Certain types of leukemia, such as acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML), can present with low white blood cell counts.

Diagnostic Approach:

The diagnosis of severe congenital neutropenia typically starts with a physical examination and symptom check. Blood tests that include a full blood count can determine the number of neutrophils, which is often low in this condition [5]. A bone marrow biopsy may also be performed to assess the production of white blood cells.

Key Diagnostic Features:

• Low levels of granulocytes (< 200/mm3) without an associated lymphocyte deficit [7]
• Presence of cytologic abnormalities and neutropenia in Pearson syndrome
• Severe combined immunodeficiency (SCID) can present with low white blood cell counts, but often involves other immune cells as well

References:

[1] Kostmann disease was first described in 1956 as an autosomal recessive disorder characterized by severe neutropenia and onset of severe infections [8]. [2] Severe congenital neutropenia is usually diagnosed before age 6 months, with cyclic neutropenia being less severe [6]. [3] The diagnosis of SCN starts with a physical exam and symptom check. Blood tests that include a full blood count can determine the number of neutrophils [5].

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