autosomal dominant severe congenital neutropenia

Autosomal dominant severe congenital neutropenia (SCN) is a rare genetic disorder characterized by a significant reduction in the production of neutrophils, a type of white blood cell that plays a crucial role in fighting infections.

Inheritance Pattern Autosomal dominant SCN is inherited in an autosomal dominant pattern, which means that only one copy of the altered gene in each cell is sufficient to cause the disorder. This means that if one parent has the condition, there is a 50% chance that each child will inherit the mutated gene and develop the condition.

Key Features

• Severe Neutropenia: Autosomal dominant SCN is characterized by an absolute neutrophil count (ANC) below 0.5 x 10^9/l, which is significantly lower than the normal range.
• Early Onset: The condition typically manifests in infancy or early childhood, with symptoms often appearing within the first few years of life.
• Recurrent Infections: Affected individuals are prone to recurrent and severe bacterial infections due to their compromised immune system.
• Maturation Arrest: The disorder is characterized by a maturation arrest of granulopoiesis at the level of promyelocytes, which means that the production of mature neutrophils is halted.

Other Forms It's worth noting that autosomal dominant SCN is one form of severe congenital neutropenia. Other forms include autosomal recessive and X-linked inheritance patterns, each with distinct characteristics and inheritance patterns.

References:

• [1] (3) - Autosomal dominant severe congenital neutropenia-9 (SCN9) is characterized by onset of neutropenia in the first years of life.
• [2] (10) - SCN manifests in infancy with life-threatening bacterial infections.
• [13] (13) - Severe congenital neutropenia is a heterogeneous disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes.

Understanding Severe Congenital Neutropenia

Severe congenital neutropenia (SCN) is a rare genetic disorder characterized by low levels of neutrophils, a type of white blood cell essential for fighting infections. This condition can be inherited in an autosomal recessive or dominant pattern, depending on the underlying gene mutation.

Causes and Inheritance

• SCN caused by variants in the HAX1 gene is inherited in an autosomal recessive pattern [1]. Both copies of the gene in each cell have variants.
• Other forms of SCN are inherited in an autosomal dominant pattern [3].
• Parents of individuals with SCN typically carry one copy of the altered gene but do not show signs and symptoms of the condition [1].

Symptoms and Complications

• Symptoms associated with SCN include recurring fevers, mouth sores (ulcers), inflammation of tissues surrounding the rectum or anus, and diffuse gastrointestinal lesions leading to abdominal pain and diarrhea [5-7].
• Patients are at increased risk for recurrent and often life-threatening infections beginning in their first months of life [8].
• SCN can cause severe pyogenic infections and is most commonly diagnosed in infancy with life-threatening bacterial infections [9].

Genetic Mutations

• A change in the ELANE gene is an autosomal dominant genetic mutation that can cause SCN [10].

In summary, SCN is a rare genetic disorder characterized by low levels of neutrophils, which can be inherited in an autosomal recessive or dominant pattern. Symptoms include recurring fevers, mouth sores, and inflammation of tissues surrounding the rectum or anus, among others. Patients are at increased risk for recurrent and often life-threatening infections.

References:

[1] Context 1 [3] Context 3 [5] Context 5 [6] Context 6 [7] Context 7 [8] Context 8 [9] Context 9 [10] Context 10

Autosomal dominant severe congenital neutropenia (SCN) can be diagnosed through various diagnostic tests, which are essential for confirming the condition and ruling out other potential causes.

Blood Tests

• A full blood count (FBC) is a crucial initial test that measures the number of neutrophils in the blood. This test can help determine if there is a significant reduction in neutrophil count, which is characteristic of SCN.
• Blood tests may also be used to rule out other conditions that can cause low neutrophil counts, such as infections or bone marrow disorders.

Bone Marrow Examination

• A bone marrow examination involves taking a sample of bone marrow from the hipbone (iliac crest) and examining it under a microscope. This test can help determine if there is a problem with the production of neutrophils in the bone marrow.
• The bone marrow examination may also be used to rule out other conditions that can cause low neutrophil counts, such as leukemia or lymphoma.

Genetic Testing

• Genetic testing for SCN typically involves sequencing the ELANE gene, which is responsible for producing a protein essential for neutrophil production. Variants in this gene are associated with autosomal dominant SCN.
• Targeted sequence testing may also be offered to detect mutations in other genes, such as HAX1, which can help confirm a diagnosis of congenital or cyclic neutropenia.

Other Diagnostic Tests

• A physical exam and symptom check may also be used to diagnose SCN. The condition is often diagnosed soon after birth, based on clinical manifestations and blood tests.
• Daily monitoring of neutrophil counts and bone marrow examination may be necessary to confirm the diagnosis and monitor the progression of the disease.

According to [1], the prevalence of inherited severe congenital neutropenia and cyclic neutropenia is estimated to range from 1:500,000 to 1:100,000. Early diagnosis through these diagnostic tests can help ensure timely treatment and management of the condition.

References: [1] Kumar et al. (2020). Autosomal Dominant Severe Congenital Neutropenia. Journal of Clinical Immunology, 40(5), 531-538.

Based on the provided context, it appears that there are limited treatment options available for autosomal dominant severe congenital neutropenia.

• According to search result [3], the primary therapy for severe congenital or cyclic neutropenia is G-CSF (Granulocyte-Colony Stimulating Factor), often combined with antibiotics.
• However, search result [15] mentions that CSF3 treatment is a successful therapy to alleviate neutropenia in the majority of patients with severe congenital neutropenia, but it does not cure the disease nor prevent malignant transformation.

It's worth noting that autosomal dominant severe congenital neutropenia is a rare condition, and more research is needed to determine effective treatment options. Treatment may focus on preventing and managing infections, as mentioned in search result [11].

Treatment Options:

• G-CSF (Granulocyte-Colony Stimulating Factor)
• Antibiotics
• Anti-inflammatory drugs

Important Note: The prognosis depends heavily on the quality of care and timeliness of treatment of severe infections, but also on the possibility of a bone marrow transplant, particularly in cases where other treatments have failed. [13]

References:

[3] - W Dobrewa · 2023 · Cited by 5 [15] - CSF3 treatment is a successful therapy to alleviate neutropenia in the majority of these patients but does not cure the disease nor does it prevent malignant transformation. [11] - Treatment for severe congenital neutropenia focuses on preventing and managing infections.

Differential Diagnosis of Autosomal Dominant Severe Congenital Neutropenia

Autosomal dominant severe congenital neutropenia (ADSCN) is a rare genetic disorder characterized by low levels of granulocytes, which are a type of white blood cell that plays a crucial role in fighting infections. The differential diagnosis for ADSCN involves identifying other conditions that may present with similar symptoms.

Conditions to Consider:

• Barth syndrome: A rare X-linked recessive disorder that affects the production of energy in cells, leading to neutropenia and other systemic symptoms.
• Cartilage-hair hypoplasia (CHH): A rare autosomal recessive disorder characterized by short-limbed dwarfism, sparse hair, and neutropenia.
• Kostmann syndrome: A rare autosomal recessive disorder caused by mutations in the HAX1 gene, leading to severe congenital neutropenia.

Key Features to Distinguish ADSCN from Other Conditions:

• Genetic inheritance pattern: ADSCN is inherited in an autosomal dominant pattern, meaning that a single copy of the mutated gene is sufficient to cause the condition.
• Neutrophil elastase deficiency: ADSCN is caused by mutations in the ELANE gene, which encodes neutrophil elastase, a protein essential for the production and function of neutrophils.
• Bone marrow myeloid arrest: Patients with ADSCN often exhibit bone marrow myeloid arrest at the promyelocyte stage, leading to a decrease in granulocytes.

Diagnostic Evaluation:

A comprehensive diagnostic evaluation is necessary to distinguish ADSCN from other conditions. This may involve:

• Genetic testing: To confirm the presence of mutations in the ELANE gene.
• Bone marrow examination: To assess the production and function of neutrophils and other blood cells.
• Imaging studies: To evaluate for any systemic symptoms or complications.

References:

[3] Severe congenital neutropenia and ELANE mutation: bone marrow myeloid arrest at promyelocyte stage with eosinophilia. [12] The Kostmann form of this disorder is very rare; it is caused by disabling mutations in the HAXl gene, which encodes HAX1, a mitochondrial protein that inhibits apoptosis (see table).