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

• AAD (Autoinflammation with Arthritis and Dyskeratosis)
• AAD Syndrome

What is Autoinflammation with Arthritis and Dyskeratosis? (Definition/Background Information)

• Autoinflammation with Arthritis and Dyskeratosis (AAD) is a rare genetic disorder characterized by recurrent episodes of fever, widespread skin dyskeratoses, arthritis, and mild autoimmunity. Other findings include eye, bone, and thyroid gland abnormalities
• The disorder is caused by mutations in the NLRP1 gene (that encodes the pyrin protein involved in regulating inflammation) and may be inherited in an autosomal dominant or autosomal recessive manner. Thus, the risk factor for Autoinflammation with Arthritis and Dyskeratosis includes a positive family history of the disorder
• AAD is typically diagnosed based on a combination of clinical examination, blood tests to measure the levels of inflammatory markers, imaging studies for bony abnormalities, and molecular genetic testing of the NLRP1 gene
• The treatment of Autoinflammation with Arthritis and Dyskeratosis is typically symptomatic and supportive and may include medications, such as non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, to reduce inflammation and prevent recurrent episodes
• Currently, there are no available measures to prevent Autoinflammation with Arthritis and Dyskeratosis as it is a genetic condition. Genetic counseling and testing may be recommended for individuals with a family history of AAD and couples planning to have children
• The prognosis of Autoinflammation with Arthritis and Dyskeratosis varies on a case-by-case basis. With suitable treatment, most affected individuals can have an improved quality of life, although the disorder can cause significant complications if left untreated. These may include failure to thrive and an enlarged spleen requiring splenectomy

Who gets Autoinflammation with Arthritis and Dyskeratosis? (Age and Sex Distribution)

• Autoinflammation with Arthritis and Dyskeratosis (AAD) is a rare disorder with congenital manifestation (onset of symptoms occur during infancy and childhood)
• It affects both males and females
• Information on the frequency of AAD and its racial/ethnic distribution is presently unavailable

What are the Risk Factors for Autoinflammation with Arthritis and Dyskeratosis? (Predisposing Factors)

The risk factors for Autoinflammation with Arthritis and Dyskeratosis include:

• Having a family history of the disorder
• Inheriting a copy of the mutated NLRP1 gene from a parent (or rarely from both parents) to develop the disorder

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 Autoinflammation with Arthritis and Dyskeratosis? (Etiology)

Autoinflammation with Arthritis and Dyskeratosis is a genetic disorder caused by mutations in the NLRF1 gene, which encodes a protein involved in the regulation of inflammation. 

• These mutations lead to abnormal functioning of the protein, resulting in recurrent inflammation and chronic symptoms
• The disorder is typically inherited in an autosomal dominant pattern
• However, two cases of double first cousins (in the same family) have been reported, making autosomal recessive inheritance a possible second mode of inheritance for the same disease

With more reported cases, the possibility of two means of inheritance may be confirmed.

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 function 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.

Autosomal recessive inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Autoinflammation with Arthritis and Dyskeratosis?

The signs and symptoms of Autoinflammation with Arthritis and Dyskeratosis include:

• Recurrent episodes of fever
• Joint pain and inflammation
• Bony abnormalities (confirmed via abnormal bone X-rays)
• Thyroiditis (thyroid inflammation)
• Skin abnormalities that may include:
  • Skin dyskeratosis, with thick adherent inflexible skin
  • Dry skin with impaired sweating
  • Brownish-purple discoloration in the skin with thickening of the dry outer layer
  • Nail dystrophy
• Eye findings are prominent and may include:
  • Sensitivity to light (photophobia)
  • Uveitis
  • Punctate keratitis
  • Corneal dyskeratosis
• Warty (non-viral) growths on the vocal cords

How is Autoinflammation with Arthritis and Dyskeratosis Diagnosed?

Autoinflammation with Arthritis and Dyskeratosis is typically diagnosed based on a combination of the following:

• Clinical examination and assessment of presenting signs and symptoms
• Evaluation of family history of the condition
• Eye examination
• Laboratory testing: Laboratory findings with elevated eosinophils, elevated inflammatory markers, reduced vitamins A, C, and retinal-binding protein, and high level of transitional B-cells in blood have been noted
• Radiological imaging studies of the abdomen and bones
• Skin biopsies, as needed
• Genetic testing for defects in the NLRP1 gene

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 Autoinflammation with Arthritis and Dyskeratosis?

Complications of Autoinflammation with Arthritis and Dyskeratosis may include 

• Failure to thrive
• Growth retardation
• Severe abnormalities of skin and eyes requiring constant care
• Chronic eye inflammation requiring frequent eye care
• Heart conduction defect 
• Enlargement of the liver and spleen (hepatosplenomegaly); enlarged spleen may require surgical removal of the spleen
• Reduced quality of life

How is Autoinflammation with Arthritis and Dyskeratosis Treated?

The treatment for Autoinflammation with Arthritis and Dyskeratosis is typically symptomatic and supportive and may include medications to reduce inflammation and prevent recurrent episodes such as the following:

• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Corticosteroids
• Interleukin-1 beta antagonists such as anakinra, rilonacept, and canakinumab

How can Autoinflammation with Arthritis and Dyskeratosis be Prevented?

Presently, it is not possible to prevent Autoinflammation with Arthritis and Dyskeratosis as the cause is a genetic mutation. 

• 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 Autoinflammation with Arthritis and Dyskeratosis? (Outcomes/Resolutions)

The prognosis for Autoinflammation with Arthritis and Dyskeratosis (AAD) depends on its severity and treatment adequacy.

• Presently, it is difficult to determine because of the small number of reported cases of AAD 
• The disorder carries significant abnormalities of bone, skin, and eye that require constant care
• With proper treatment and supportive care, the prognosis of AAD may be improved

Additional and Relevant Useful Information for Autoinflammation with Arthritis and Dyskeratosis:

The following link is a useful resource for information on other rare conditions on DoveMed:

https://www.dovemed.com/diseases-conditions/rare-disorders/