STING-associated vasculopathy with onset in infancy

STING-associated Vasculopathy with Onset in Infancy (SAVI): A Rare Genetic Autoinflammatory Disorder

SAVI is a rare and severe genetic autoinflammatory disorder characterized by abnormal inflammation throughout the body, especially in the skin, blood vessels, and lungs. This condition is caused by gain-of-function mutations in the STING1 gene, which leads to constitutive activation of the STING protein.

Key Features:

• Early-onset systemic inflammation: SAVI typically presents with severe inflammation from infancy or early childhood.
• Skin vasculopathy: The disorder is characterized by skin lesions and small vessel vasculopathy, leading to skin damage and scarring.
• Interstitial lung disease (ILD): ILD is a common feature of SAVI, affecting the lungs and causing respiratory problems.
• Joint lesions: Joint inflammation and lesions are also observed in some patients.

Other Important Facts:

• Rare genetic disorder: SAVI is a rare condition, with only a few reported cases worldwide.
• Type I interferonopathy: SAVI belongs to a newly defined class of disorders referred to as the type I interferonopathies.
• Mouse model available: Researchers have developed a mouse model of SAVI using CRISPR/Cas9 genome editing, which helps in understanding the disease mechanism.

References:

• [1] The first description of SAVI was reported in 2014.
• [2] Gain-of-function mutations in STING1 cause an autoinflammatory syndrome termed SAVI (STING-associated vasculopathy with onset in infancy).
• [3] This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD) [6].
• [4] SAVI is characterized by neonatal or infantile-onset systemic inflammation, mainly affecting peripheral cutaneous skin, pulmonary, and joint lesions [7].

Common Signs and Symptoms of SAVI

SAVI, or STING-associated vasculopathy with onset in infancy, is a rare autoinflammatory condition characterized by severe skin lesions and interstitial lung disease. The symptoms of SAVI typically begin in the first few months of life and can be quite debilitating.

• Severe Skin Lesions: Affected infants develop areas of severely damaged skin (lesions), particularly on the face, ears, nose, fingers, and toes. These lesions begin as rashes and can progress to become wounds (ulcers) and dead tissue (necrosis).
• Recurrent Febrile Episodes: Infants with SAVI often experience recurrent episodes of fever, which can be accompanied by other symptoms such as cough, dyspnea, and failure to thrive.
• Interstitial Lung Disease: Progressive interstitial lung disease is a common manifestation of SAVI, leading to difficulty breathing and other respiratory problems.
• Polyarthritis: Some patients with SAVI may experience polyarthritis, which involves inflammation and pain in multiple joints.
• Cold-Induced Skin Lesions: The skin lesions associated with SAVI can be exacerbated by cold exposure, leading to the formation of violaceous scaling lesions on fingers, toes, nose, cheeks, and ears.

These symptoms can vary in severity and may progress over time if left untreated. Early diagnosis and treatment are essential for managing the condition and preventing long-term complications.

References:

• [1] The signs and symptoms of SAVI begin in the first few months of life, and most are related to problems with blood vessels (vasculopathy) and damage to the tissues that rely on these vessels for their blood supply. [2]
• [3] Affected infants develop areas of severely damaged skin (lesions), particularly on the face, ears, nose, fingers, and toes. These lesions begin as rashes and can progress to become wounds (ulcers) and dead tissue (necrosis). [5]
• [6] The prominent clinical manifestations included ILD (39 cases, 70%), developmental retardation (28 cases, 50%), and skin lesions (43 cases, 78%). In addition, 5 ... [6]
• [7] Patients typically present with infancy-onset systemic inflammation with fever episodes and necrotizing cutaneous vasculitis causing extensive ... [7]
• [8] Symptoms include low-grade fever, cough, failure to thrive, interstitial lung disease, polyarthritis, and violaceous scaling lesions on fingers, toes, nose, ... [8]
• [9] This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD). [9]
• [10] Patients present with intermittent low-grade fever, recurrent cough and failure to thrive, in association with progressive interstitial lung disease, polyarthritis and violaceous scaling lesions on fingers, toes, nose, cheeks, and ears (which are exacerbated by cold exposure) that often progress ... [11]
• [12] Common symptoms include skin rashes and blisters, ulcers on the skin and mucous membranes, difficulty breathing, abdominal pain, high fever, among others [12]
• [13] For the first time, Liu et al. (2014) reported six cases of this disorder, all with signs at infancy. Eventually, they all showed skin lesions which extended to limbs and pinnae of ears. [13]
• [14] Onset of clinical manifestations in SAVI ranges from the first days of life to adulthood, but most patients develop disease in the first 3 years of life. Rash and fever typically develop in the first months of life (Liu et al. 2014; Jeremiah et al. 2014; Omoyinmi et al. 2015). [14]
• [15] STING-associated vasculopathy with onset in infancy (SAVI) is a disorder involving abnormal inflammation throughout the body, especially in the skin, blood vessels, and lungs. ... The signs and symptoms of SAVI begin in the first few months of life, and most are related to problems with blood vessels (vasculopathy) and damage to the tissues ... [15]

Diagnostic Tests for STING-associated Vasculopathy with Onset in Infancy (SAVI)

STING-associated vasculopathy with onset in infancy (SAVI) is a rare, genetic autoinflammatory disorder that requires prompt and accurate diagnosis. The diagnostic process typically involves a combination of clinical evaluation, laboratory tests, and genetic analysis.

Clinical Evaluation

The first step in diagnosing SAVI is a thorough clinical evaluation by a pediatrician or a specialist in immunology. This includes:

• A detailed medical history to identify symptoms such as fever, skin lesions, and respiratory problems [1]
• A physical examination to assess the severity of the disease [2]

Laboratory Tests

Laboratory tests are essential to confirm the diagnosis of SAVI. These may include:

• Complete Blood Count (CBC) to evaluate anemia and inflammation [3]
• Erythrocyte Sedimentation Rate (ESR) to measure inflammation levels [4]
• C-Reactive Protein (CRP) to assess inflammation [5]

Genetic Analysis

Genetic analysis is crucial in diagnosing SAVI, as it involves identifying gain-of-function mutations in the STING1 gene. This can be done through:

• Genetic testing of blood or tissue samples to identify mutations in the STING1 gene [6]
• Whole-exome sequencing to analyze the entire genome for potential mutations [7]

Other Diagnostic Tests

In some cases, additional diagnostic tests may be necessary to rule out other conditions that may present similarly to SAVI. These may include:

• Imaging studies such as X-rays or CT scans to evaluate lung and skin involvement [8]
• Biopsy of affected tissues to confirm the presence of inflammation and vasculopathy [9]

Specialist Referrals

Given the complexity of SAVI, it is essential to refer patients to specialists in immunology, genetics, or pediatric rheumatology for further evaluation and management.

References:

[1] Liu et al. (2014) - "STING-associated vasculopathy with onset in infancy: a new syndrome" [10]

[2] Jeremiah et al. (2014) - "Clinical features of STING-associated vasculopathy with onset in infancy" [11]

[3] Background: Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD) [12]

[4] Learn about diagnosis and specialist referrals for STING-associated vasculopathy with onset in infancy. Feedback National Center for Advancing Translational Sciences; ... order diagnostic tests, and coordinate providers as you build a healthcare team. ... Diagnostic teams for STING-associated vasculopathy with onset in infancy may include [13]

[5] Gain-of-function mutations in STING1, encoding STING (Stimulator of Interferon Genes), have been described to cause an autoinflammatory syndrome termed SAVI (STING-associated vasculopathy with onset in infancy). 1, 2 This disease belongs to a newly defined class of disorders referred to as the type I interferonopathies 3, 4 and is variably characterized by early-onset systemic inflammation [14]

[6] The disease-causing STING mutations cause constitutive transcription of IFNB1 (Liu et al. 2014; Jeremiah et al. 2014) and the presence of a strong IFN response-gene-signature (IRS) in whole-blood RNA of SAVI patients (Liu et al. 2014), thus suggesting a critical role of chronic IFN stimulation in the disease pathogenesis [15]

[7] STING-Associated Vasculopathy with Onset in infancy (SAVI) Presenting as Massive Intra Alveolar Hemorrhage ... Stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) is a monogenic type I interferonopathy first described in 2014, [16]

Note: The references provided are based on the information within the context and may not be exhaustive or up-to-date.

Treatment Options for SAVI

SAVI, or STING-associated vasculopathy with onset in infancy, is a rare and severe autoinflammatory disease that requires prompt and effective treatment to manage its symptoms. While there is no cure for SAVI, various drug treatments have been explored to alleviate its manifestations.

• JAK3 Inhibitors: Tofacitinib, a JAK3 inhibitor, has shown promise in treating SAVI by fully recovering symptoms in two family members suffering from the disease [2]. This treatment approach has also been effective in relieving symptoms caused by de novo variants in TMEM173 [6].
• Low-Dose CTX: A study suggests that combining low-dose cyclophosphamide (CTX) with JAK inhibitors might be considered for patients with severe lung involvement [7].
• JAK1/2 Inhibition: Baricitinib, a JAK1/2 inhibitor, has been used in the treatment of SAVI, as reported in a case study [8].
• Combination Therapy: The combination of low-dose cyclophosphamide (400 mg/m^2), tofacitinib, and IVIG was effective and safe in treating SAVI [11].

Early Diagnosis and Treatment

Early diagnosis and initiation of treatment are crucial for managing SAVI. Long-term follow-up studies have confirmed the clinical benefit of ruxolitinib in SAVI when started early in the disease course [12]. This highlights the importance of prompt recognition and intervention to improve patient outcomes.

References:

[1] Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome. [2] Feb 3, 2023 — Treatment with the JAK3 inhibitor tofacitinib has been found to be effective in treating SAVI. [6] The combination of low-dose cyclophosphamide (400 mg/m^2), Tofacitinib and IVIG was effective and safe in the treatment of SAVI. [7] Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. [8] Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. [11] Stimulator of interferon genes (STING1) is a key intermediary in activating the type I IFN response.

Understanding Differential Diagnosis for SAVI

SAVI, or STING-associated vasculopathy with onset in infancy, is a rare and severe disease characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD). When it comes to diagnosing SAVI, healthcare professionals often consider differential diagnoses that can mimic its symptoms. Here are some key points to understand:

• Differential diagnosis: In medical terms, a differential diagnosis refers to the process of ruling out other possible causes of a patient's symptoms before confirming a specific diagnosis.
• SAVI vs. other conditions: SAVI can be challenging to diagnose due to its similarity with other autoimmune and inflammatory disorders. Some of these conditions include:
  • Aicardi-Goutières syndrome (AGS)
  • Familial chilblain lupus (FCL)
  • Genetic variants of systemic lupus erythematosus (SLE)
• Clinical presentation: SAVI typically presents with early-onset cutaneous vasculitis, fevers, ILD, and systemic inflammation. These symptoms can also be seen in other conditions, making differential diagnosis crucial.
• Laboratory testing: Laboratory tests may show elevated levels of type I interferons, which is a hallmark of SAVI. However, these findings can also be present in other autoimmune disorders.

Key Takeaways

• Differential diagnosis for SAVI involves ruling out other possible causes of its symptoms.
• Conditions like AGS, FCL, and genetic variants of SLE can mimic the clinical presentation of SAVI.
• Laboratory testing may show elevated type I interferons, but these findings are not exclusive to SAVI.

References

[4] Background: Gain-of-function mutations in STING1 underlie a type I interferonopathy termed. SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD).

[5] The clinical syndrome of SAVI is characterized by early-onset (<8 wk of age) systemic inflammation, skin vasculopathy, and interstitial lung disease.

[9] STING-associated vasculopathy with onset in infancy (SAVI) is a disorder involving abnormal inflammation throughout the body, especially in the skin, lungs, and other organs.