What age do people get VEXAS syndrome? An overview of onset age

VEXAS syndrome is an adult-onset disease, with studies reporting a median age of symptom onset in the mid-60s, predominantly affecting males over 50 years of age. This recently identified condition, first described in 2020, presents a significant challenge in senior care, prompting the question: What age do people get VEXAS syndrome?

Quick Summary

A late-onset inflammatory disorder, VEXAS syndrome most frequently affects men over the age of 50, with reported median ages at symptom onset often falling between 64 and 69 years, although the age range can extend significantly.

Key Points

• Median Age of Onset: VEXAS syndrome typically presents in mid-to-late adulthood, with a median age at symptom onset often in the mid-60s, though it can vary significantly among individuals.

• Primarily Affects Older Males: The disease predominantly affects males over 50 due to an X-linked somatic mutation in the UBA1 gene.

• Broad Age Range: While the median age is in the 60s, documented cases show a wide age range from the 40s to the 80s and beyond.

• Acquired Genetic Cause: Unlike inherited genetic diseases, the somatic mutation causing VEXAS is acquired over a person's lifetime, explaining its late-life manifestation.

• Diagnosis Challenges: The syndrome's symptoms overlap with many other inflammatory and hematological conditions, making accurate and timely diagnosis challenging, especially in older patients.

Understanding the Typical Onset Age

While the exact age of diagnosis varies, VEXAS syndrome is characterized as a late-adulthood condition. The median age at symptom onset is consistently reported in medical literature as being in the mid-to-late 60s. For instance, a study published in the New England Journal of Medicine reported a median age of 64 among the initial cohort of male patients. This does not mean it cannot occur earlier, but it is highly atypical to see cases in young adults. The disease arises from a somatic mutation, meaning it is an acquired genetic change over a lifetime rather than an inherited one, which explains its later-life manifestation.

The Full Age Range

Although the median age provides a central point, the full age range for VEXAS syndrome is broad. Cases have been documented in patients as young as 40 and as old as 90. It is important for clinicians to consider VEXAS in older individuals experiencing unexplained systemic inflammation, even if they are outside the typical median age. The accumulation of the somatic UBA1 gene mutation in hematopoietic stem cells is a gradual process, and the development of clinical symptoms can occur at different points in late adulthood for each individual.

Why Older Age and Male Predominance?

There is a strong correlation between older age and male gender in VEXAS syndrome due to the underlying genetics. The condition is caused by a somatic mutation in the UBA1 gene, which is located on the X chromosome.

• X-linked nature: Since males typically have only one X chromosome, a mutation in the UBA1 gene is more likely to cause symptoms. Females, with two X chromosomes, are generally protected unless they have a rare condition called monosomy X or a specific mosaicism.
• Acquired mutation: The mutation is not inherited but occurs spontaneously within a person's blood-forming cells over time. This process, known as clonal hematopoiesis, becomes more common with advancing age, which is why the disease manifests later in life.

Common Signs and Symptoms in Older Adults

The clinical presentation of VEXAS syndrome can be highly variable and mimic many other inflammatory or hematological conditions, making diagnosis difficult. Older patients, especially males, with unexplained and persistent systemic inflammation should be evaluated for VEXAS. Key symptoms include:

• Recurrent Fevers: Unexplained fevers that come and go, often accompanied by general fatigue and a feeling of being unwell.
• Dermatological Issues: Various types of skin rashes, including neutrophilic dermatoses like Sweet's syndrome.
• Hematological Problems: Myelodysplastic syndrome (MDS), macrocytic anemia, or thrombocytopenia are frequently observed.
• Cartilage Inflammation: Relapsing polychondritis, which causes inflammation of cartilage, particularly in the ears and nose.
• Pulmonary Infiltrates: Inflammation in the lungs, leading to respiratory symptoms like cough and shortness of breath.
• Vascular Inflammation: Vasculitis, or inflammation of blood vessels, and thrombotic events like deep vein thrombosis (DVT).
• Ocular Inflammation: Inflammation of the eyes, including episcleritis, scleritis, and uveitis.

The Importance of a Genetic Test

Given its overlap with other diseases, definitive diagnosis relies on genetic testing to confirm the UBA1 mutation. For older males with chronic, unexplained inflammatory symptoms, particularly those who have responded poorly to conventional treatments, genetic testing is critical for accurate diagnosis and appropriate management. Early identification is key to improving outcomes.

The Diagnostic Pathway for VEXAS Syndrome

1. Clinical Suspicion: A physician, often a rheumatologist or hematologist, develops suspicion based on a patient's age, gender, and combination of unexplained inflammatory and hematological symptoms.
2. Laboratory Findings: Blood tests show elevated inflammatory markers (CRP, ESR) and potential hematological abnormalities like macrocytic anemia or low blood counts.
3. Bone Marrow Evaluation: A bone marrow biopsy can reveal cytoplasmic vacuoles in myeloid and erythroid precursor cells, which are characteristic of VEXAS.
4. Genetic Confirmation: Genetic testing is performed to detect the somatic UBA1 gene mutation, which confirms the diagnosis.

Distinguishing VEXAS from Other Senior Inflammatory Conditions

Feature	VEXAS Syndrome	Other Adult-Onset Inflammatory Conditions	Polymyalgia Rheumatica (PMR)	Systemic Lupus Erythematosus (SLE)	Relapsing Polychondritis	Myelodysplastic Syndromes (MDS)
Typical Onset Age	>50 years old (median 60s)	Variable	>50 years old (median 70s)	Any age, but most commonly 15-44	Variable	>60 years old
Genetics	Somatic UBA1 mutation	Often polygenic or unknown	Unknown	Likely polygenic/multifactorial	Unknown	Somatic mutations
Common Symptoms	Fever, skin issues, chondritis, macrocytic anemia, vasculitis	Depends on specific disease	Muscle pain, stiffness, fever	Rash, joint pain, fatigue, fever, organ damage	Cartilage inflammation, ocular inflammation	Low blood counts, fatigue
Response to Steroids	Often dependent, poor long-term response	Variable	Good, rapid response	Highly variable	Can be effective, but often relapses	Not treated with steroids alone
Key Laboratory Finding	Elevated CRP/ESR, macrocytic anemia, vacuoles in bone marrow	Elevated CRP/ESR, specific autoantibodies	Elevated CRP/ESR	Positive ANA, specific autoantibodies	Elevated CRP/ESR	Cytopenias

Conclusion: A Late-Life Diagnostic Consideration

Since its discovery, VEXAS syndrome has redefined the understanding of adult-onset autoinflammatory diseases. The key takeaway regarding age is that while it is not a childhood disease, its onset is variable within late adulthood, primarily affecting men over 50. The median onset age in the mid-60s emphasizes that healthcare providers should be vigilant for this diagnosis when faced with older male patients exhibiting unexplained inflammation and blood abnormalities. Considering a genetic cause for a late-onset, severe inflammatory condition is a relatively new concept that highlights the importance of keeping abreast of new medical findings. Continued research is vital for improving our understanding of this complex disease. An excellent resource for more information can be found on the National Institutes of Health website at https://www.ncbi.nlm.nih.gov/books/NBK614471/.

Frequently Asked Questions

What is the youngest age VEXAS syndrome can start?

While the median age of onset is in the mid-60s, VEXAS syndrome has been documented in individuals as young as 40, though such cases are less common than in older adults. Onset is rare before the fifth decade of life.

Why is VEXAS syndrome so strongly linked to older age?

VEXAS is a somatic condition, meaning it is caused by a genetic mutation acquired during one's lifetime, not inherited. The accumulation of this mutation in blood-forming cells is a process that typically occurs with advancing age, making it a disease of late adulthood.

Does VEXAS syndrome affect men and women at the same age?

VEXAS primarily affects males due to its X-linked nature. In the rare instances it affects females, it is typically in late adulthood, but the prevalence is much lower. Women are often protected by having a second, functional X chromosome.

Are there any factors besides age that influence the onset of VEXAS?

Besides being a male over 50, other factors can influence the diagnosis, including pre-existing conditions like myelodysplastic syndrome (MDS) or certain inflammatory disorders. The underlying UBA1 mutation is the direct cause, but its expression is complex.

Can younger people be tested for the VEXAS mutation?

Genetic testing can be performed on individuals of any age. However, testing is generally reserved for adult patients, most commonly males over 50, who present with the specific constellation of unexplained inflammatory and hematological symptoms suggestive of VEXAS syndrome.

How does the age of onset impact the diagnosis of VEXAS?

Because VEXAS is a late-onset disease, its symptoms in older adults can be easily mistaken for other more common age-related conditions. This can lead to significant delays in diagnosis, with patients often receiving incorrect or incomplete treatments before VEXAS is considered.

Is the prognosis for VEXAS syndrome related to the age of onset?

The age of onset may impact the overall prognosis, as older patients may have additional comorbidities that complicate the disease course. However, VEXAS syndrome itself is known to be a severe, progressive condition with a high mortality rate, regardless of when symptoms first appear.