What are the other Names for this Condition? (Also known as/Synonyms)

• SAMD9-AID
• SAMD9L Ataxia-Pancytopenia Syndrome
• SAMD9L-AID (SAMD9L-Associated Autoinflammatory Disease)

What is SAMD9L-Associated Autoinflammatory Disease? (Definition/Background Information)

• SAMD9L-Associated Autoinflammatory Disease (SAMD9L-AID) is an extremely rare genetic disorder characterized by recurrent episodes of inflammation that affect multiple organs and systems in the body. These include the adrenal glands, testes, ovaries, thymus, and the cerebellum of the brain. Developmental delays are also commonly noted
• SAMD9L-AID is caused by mutations in the SAMD9L gene, which provides instructions for making the SAMD9L protein that is important in regulating the immune system activity. When this protein is not functioning properly, it can lead to recurrent episodes of inflammation and damage to various organs and tissues
• The main risk factor for SAMD9L-Associated Autoinflammatory Disease is having a family history of the disorder. It is inherited in an autosomal dominant manner, which means that an individual must inherit one copy of the mutated SAMD9L gene from either parent to develop the condition. SAMD9 and SAMD9L syndromes have been seen in individuals with partial and complete monosomy 7 syndrome
• SAMD9L-Associated Autoinflammatory Disease is diagnosed through a combination of genetic testing, physical examination, and imaging studies. A blood test can be done to detect the presence of the mutated SAMD9L gene, and imaging studies, such as CT or MRI scan studies, can be used to observe the extent of internal organ involvement
• The treatment of SAMD9L-Associated Autoinflammatory Disease is primarily focused on managing the symptoms and correcting any deficiencies in the immune system. The prognosis for SAMD9L-AID is uncertain as the disorder is extremely uncommon. However, per available reports, the outcomes are generally unfavorable; deaths have been reported in childhood

Who gets SAMD9L-Associated Autoinflammatory Disease? (Age and Sex Distribution)

• SAMD9L-Associated Autoinflammatory Disease is extremely rare, and only a few cases have been reported worldwide
• This genetic disorder is manifested congenitally (at birth), and both males and females may be affected
• No information is presently available on worldwide distribution and racial/ethnic groups at risk for the disorder

What are the Risk Factors for SAMD9L-Associated Autoinflammatory Disease? (Predisposing Factors)

The risk factors for SAMD9L-Associated Autoinflammatory Disease (SAMD9L-AID) may include:

• The primary risk factor is a family history of the disorder. Individuals with a parent or sibling with SAMD9L-AID are at a higher risk for inheriting the condition
• Inheriting one copy of the mutated SAMD9L gene from a parent to develop the disorder
• Individuals with partial or complete monosomy 7 syndrome are at higher risk for SAMD9 and SAMD9L syndromes

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of SAMD9L-Associated Autoinflammatory Disease? (Etiology)

SAMD9L-Associated Autoinflammatory Disease (SAMD9L-AID) is caused by mutations in the SAMD9L gene, which provides instructions for making a protein called sterile alpha motif domain-containing 9-like protein (SAMD9L).

• This protein plays a critical role in regulating the activity of the immune system and preventing the overproduction of inflammatory molecules
• When this protein is not functioning properly, it can lead to recurrent episodes of inflammation and damage to various organs and tissues
• Partial or complete monosomy 7 syndrome makes an expression of the SAMD9 and SAMD9L-AID more likely because the individual will not have a normal chromosome 7 to minimize or prevent expression of the condition
• The SAMD9 gene is near the SAMD9L gene. When SAMD9 is affected, the syndrome is similar but more severe. Both genes are located on chromosome 7

SAMD9L-AID is inherited in an autosomal dominant manner.

Autosomal dominant mode of inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly functioning gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition, or pass it on to their offspring.

What are the Signs and Symptoms of SAMD9L-Associated Autoinflammatory Disease?

The signs and symptoms of SAMD9L-Associated Autoinflammatory Disease can vary widely between individuals, and it can be mild or severe. In general, the common signs and symptoms include:

• Intrauterine growth retardation (IUGR) and failure to thrive (FTT)
• Anemia, thrombocytopenia (low platelets), and leukopenia (low white blood cells)
• Susceptibility to infections
• Speech and language delays
• Inability to maintain balance (ataxia)
• Involuntary and rapid vertical or horizontal eye movements (nystagmus)
• Many organs can be affected by hypoplasia (underdevelopment)
• In addition to low production of blood components, a transition to leukemia may take place

Some individuals have a spontaneous improvement in the cytopenias (low formation of red blood cells, white blood cells, and platelets) on the basis of spontaneous reversion of the defective gene. This leads to a milder disease course.

How is SAMD9L-Associated Autoinflammatory Disease Diagnosed?

SAMD9L-Associated Autoinflammatory Disease is diagnosed through a combination of the following tests and procedures:

• Physical examination and assessment of presenting signs and symptoms
• Evaluation of family history of the condition
• Radiological imaging studies, such as CT or MRI scans, can be used to identify internal organ abnormalities
• Bone marrow testing to determine the extent and cause of the decrease in blood components
• A blood test can be done to detect the presence of the mutated SAMD9L gene
• Genetic testing will be done to search for complete or partial monosomy 7 or translocations of chromosome 7

SAMD9L can cause intrauterine growth retardation. The hematologic effects can be detected following 3 months of pregnancy. Hence, the diagnosis is typically made very early in life.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of SAMD9L-Associated Autoinflammatory Disease?

The complications of SAMD9L-Associated Autoinflammatory Disease can include:

• Pancytopenia from decreased levels of red blood cells, white blood cells, and platelets
• Neurological complications, such as balance disorders, abnormal eye movements, and developmental delays
• Severe infections combined with the body’s inability to fight the infections
• Bleeding disorders
• Bone marrow failure to produce red blood cells, white blood cells, and platelets, along with a risk for acute myeloid leukemia, termed myelodysplastic syndrome (MDS)
• Lymphoma
• Complications from the underdeveloped thymus, thyroid, ovaries, and testes

Some families with balance problems and nystagmus from cerebellar atrophy may carry SAMDL9 mutations with less severe symptoms.

How is SAMD9L-Associated Autoinflammatory Disease Treated?

There is currently no specific treatment for SAMD9L-Associated Autoinflammatory Disease, and treatment is primarily focused on managing symptoms.

• Red blood cell, white blood cell, or platelet transfusions as necessary to temporarily correct deficiencies
• Prompt institution of antibiotics for infections
• Bone marrow transplantation or chemotherapy for myelodysplasia or leukemia
• Thyroid studies with supplementation if required
• Speech and hearing therapy for language delay
• Nutritional support for poor weight gain

If thrombocytopenia is present, non-steroidal anti-inflammatory drugs (NSAIDs) and anticoagulants have to be avoided.

How can SAMD9L-Associated Autoinflammatory Disease be Prevented?

Presently, it is not possible to prevent IL-18 Mediated PAP and Recurrent MAS as the cause is due to genetic factors.

• Genetic counseling and testing may be recommended for individuals with a family history of the disorder and couples planning to have children
• However, early diagnosis and appropriate treatment can help manage the symptoms and prevent complications

What is the Prognosis of SAMD9L-Associated Autoinflammatory Disease? (Outcomes/Resolutions)

The prognosis for SAMD9L-Associated Autoinflammatory Disease may depend on its severity and treatment response.

• Presently, it is not possible to determine the prognosis based on a few reported cases; also, little is known about its long-term effects
• Generalizations about the disease course must therefore be cautious. Many of the reported cases had unfavorable outcomes; early deaths during childhood were observed

Additional and Relevant Useful Information for SAMD9L-Associated Autoinflammatory Disease:

If the SAMD9 gene is affected (and not the SAMD9L gene), the syndrome is typically worse. Such individuals may have the MIRAGE syndrome with:

• Myelodysplasia
• Infections
• Restriction of growth
• Adrenal hypoplasia 
• Genital phenotypes
• Enteropathy

On the whole, this disease manifests and is managed as SAMD9L.