X-linked severe congenital neutropenia

X-linked severe congenital neutropenia is an immunodeficiency syndrome characterized by recurrent major bacterial infections, severe congenital neutropenia, and monocytopenia.

Common Signs and Symptoms:

• Recurring fevers [5]
• Mouth sores (ulcers) [5]
• Inflammation of the tissues that surround the umbilical cord stump [4]
• Abscesses (or boils) on the skin [4]
• Oral infections [4]
• Pneumonia [8, 9]
• Diffuse gastrointestinal lesions leading to abdominal pain and diarrhea [9]

Other Possible Symptoms:

• Erosive gingivitis, hemorrhage, and pain associated with papilla on the tongue and mucous membranes [11]
• Stomatological signs are almost always present after 2 years of age [11]

These symptoms can occur due to the body's inability to fight off infections caused by low levels of granulocytes (a type of white blood cell). The condition is usually diagnosed during early childhood, with some cases being identified in neonates.

References:

• [4] Apr 1, 2019
• [5] Apr 27, 2022
• [8] by J Skokowa · 2017 · Cited by 370
• [9] by J Donadieu · 2011 · Cited by 292
• [11] This neutropenia leads to repeated bacterial or mycotic infections in various locations, mostly cutaneo-mucous, ear, nose, and throat, and pulmonary. Stomatological signs are almost always present after 2 years of age and are distinguished by erosive gingivitis, hemorrhage and pain, associated with papilla on the tongue and mucous membranes.

Diagnostic Tests for X-linked Severe Congenital Neutropenia

X-linked severe congenital neutropenia (XLSCN) is a rare genetic disorder characterized by low levels of neutrophils, a type of white blood cell necessary for fighting infections. Accurate diagnosis is crucial to initiate appropriate treatment and management.

Diagnostic Tests:

• Bone Marrow Biopsy: A bone marrow biopsy can be very helpful in the diagnosis of severe congenital neutropenia. Bone marrow is also necessary to rule out malignant conditions [9].
• Genetic Testing: Genetic testing, specifically sequencing of the WAS gene (Xp11.23), is recommended for diagnosing XLSCN [6]. This test can identify disease-causing variants in the WAS gene.
• Clinical Genetic Test: A clinical genetic test offered by Intergen includes assessment of non-coding variants and is ideal for patients with congenital neutropenia or a clinical suspicion of cyclic neutropenia [7].
• Whole-Exome Sequencing: Whole-exome sequencing, including assessment of non-coding variants, can be performed to identify disease-causing variants in genes such as ELANE, HAX1, and others [8].

Diagnostic Teams:

A diagnostic team for X-linked severe congenital neutropenia may include:

• Genetics
• Immunology
• Hematology

These teams work together to provide a comprehensive diagnosis and develop an appropriate treatment plan.

References: [9] Dec 20, 2022 — Bone marrow biopsy can be very helpful in the diagnosis of severe congenital neutropenia. [6] Clinical Genetic Test offered by Intergen for conditions (1): X-linked severe congenital neutropenia; Testing genes (1): WAS (Xp11.23); [7] Nov 13, 2023 — A 28 gene panel that includes assessment of non-coding variants. Is ideal for patients with congenital neutropenia or a clinical suspicion of cyclic ... [8] by SN McNulty · 2021 · Cited by 6 — We describe clinically validated assay developed for assessing patients with suspected SCN. The assay is performed from a whole-exome backbone. [10] A PCP can help you get specialist referrals, including Genetics and Immunology.

Treatment Options for X-linked Severe Congenital Neutropenia

X-linked severe congenital neutropenia (SCN) is a rare and serious immunodeficiency disorder characterized by recurrent major bacterial infections, severe congenital neutropenia, and monocytopenia. While there are no specific treatments that can cure this condition, various drug therapies have been explored to manage its symptoms and prevent complications.

• Granulocyte Colony-Stimulating Factor (G-CSF): G-CSF is a recombinant protein that stimulates the production of neutrophils in the bone marrow. It has been shown to be effective in increasing neutrophil counts and reducing the frequency and severity of infections in patients with SCN [8]. The dosage of G-CSF may need to be gradually increased to normalize neutrophil counts, and it is often combined with antibiotics for optimal results.
• Hematopoietic Stem Cell Transplants: In cases where G-CSF therapy is ineffective or not tolerated, hematopoietic stem cell transplants (HSCTs) are considered as a treatment option. HSCTs involve replacing the patient's bone marrow with healthy stem cells from a donor [4].
• Antimicrobial Prophylaxis: To prevent infections, antimicrobial prophylaxis is recommended for patients with SCN. Trimethoprim-sulfamethoxazole (TMP-SMX) is commonly used as a once-daily dose of 50 mg/kg/d to partially prevent infections [6].

Newer Therapeutic Agents

• Mavorixafor: Mavorixafor, a newer medication under investigation for severe congenital neutropenia, has shown promise in increasing neutrophil counts and reducing the risk of infections. However, more research is needed to confirm its efficacy and safety in patients with SCN [9].

Important Considerations

• Genetic Counseling: Patients with SCN should undergo genetic counseling to understand the inheritance pattern of this condition and the risks associated with it.
• Regular Monitoring: Regular monitoring of neutrophil counts, infection frequency, and overall health is essential for managing SCN effectively.

In summary, while there are no specific treatments that can cure X-linked severe congenital neutropenia, various drug therapies such as G-CSF, antimicrobial prophylaxis, and hematopoietic stem cell transplants have been explored to manage its symptoms and prevent complications.

Differential Diagnosis of X-linked Severe Congenital Neutropenia

X-linked severe congenital neutropenia (SCN) is a rare genetic condition characterized by low levels of granulocytes. The differential diagnosis for XLT includes several conditions that can present with similar symptoms.

• GATA1-related X-linked cytopenia: This condition is characterized by thrombocytopenia and/or anemia ranging from mild to severe, along with one or more of the following: platelet dysfunction, mild beta-thalassemia, neutropenia, and congenital erythropoietic porphyria in males. Thrombocytopenia typically presents in infancy.
• Wiskott-Aldrich syndrome: This is a rare genetic disorder that affects the immune system and can present with thrombocytopenia, eczema, and recurrent infections.
• X-linked thrombocytopenia (XLT): This condition is characterized by low platelet count and can be associated with other symptoms such as anemia, neutropenia, and congenital erythropoietic porphyria.

Key Points to Consider

• The differential diagnosis for XLT includes several conditions that can present with similar symptoms.
• GATA1-related X-linked cytopenia is characterized by thrombocytopenia and/or anemia ranging from mild to severe.
• Wiskott-Aldrich syndrome is a rare genetic disorder that affects the immune system and can present with thrombocytopenia, eczema, and recurrent infections.
• X-linked thrombocytopenia (XLT) is characterized by low platelet count and can be associated with other symptoms such as anemia, neutropenia, and congenital erythropoietic porphyria.

References

[6] Diagnostic Considerations · Large granular lymphocyte leukemia · Autoimmune diseases · Chronic myelomonocytic leukemia · Congenital neutropenia. [11] The differential diagnosis for XLT includes GATA1-related X-linked cytopenia, which is characterized by thrombocytopenia and/or anemia ranging from mild to severe and one or more of the following: platelet dysfunction, mild beta-thalassemia, neutropenia, and congenital erythropoietic porphyria in males. [14] The WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes caused by pathogenic variants in WAS.