On this page
PAPA syndrome
PAPA syndrome is a rare genetic condition causing the body's immune system to overreact, leading to inflammation in joints, skin, and sometimes other areas. It primarily affects individuals from childhood, causing painful and debilitating symptoms.
Overview
PAPA syndrome, which stands for Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne, is a rare autoinflammatory disorder. Autoinflammatory conditions occur when the innate immune system, the body's first line of defence, becomes overactive and causes recurrent episodes of inflammation without an apparent trigger or infection [PMID:33674684]. In PAPA syndrome, this can lead to painful joint inflammation (arthritis), chronic skin ulcers called pyoderma gangrenosum, and severe cystic acne.
The condition typically manifests in childhood, often with joint inflammation as the initial symptom. The severity of symptoms can vary significantly among affected individuals, even within the same family [PMID:19166668]. PAPA syndrome is considered rare, though its exact prevalence in the UK population is not well established.
Symptoms & clinical features
The primary features of PAPA syndrome are joint inflammation, specific skin lesions, and severe acne. Joint involvement often presents as episodes of sterile arthritis, meaning there is inflammation within the joint fluid but no bacterial infection [PMID:19166668]. These episodes can be very painful, leading to swelling and reduced movement, and may recur over time. Repeated episodes of arthritis can sometimes cause joint damage if not managed appropriately.
Pyoderma gangrenosum refers to painful skin ulcers that can develop, often starting as small bumps or pustules before progressing into deep, destructive sores. These lesions commonly appear on the legs but can affect any part of the body. Severe cystic acne, which is a more aggressive and painful form of acne, typically appears during adolescence and can lead to scarring. While these three symptoms give the syndrome its name, not everyone with PAPA syndrome will experience all of them, and their severity can differ.
Video: Genetics 101
Affected organs
PAPA syndrome primarily affects the joints and the skin. The joints, particularly larger ones such as knees, ankles, and elbows, are frequently inflamed during arthritic episodes. This inflammation can sometimes lead to damage to the joint cartilage and bone over time. The skin is affected by pyoderma gangrenosum, which are painful ulcers that heal slowly and can leave scars, and by severe cystic acne, typically on the face, chest, and back.
While less common, some individuals may also experience inflammation in other areas. The severity and combination of affected organs can vary widely between individuals, even within the same family.
Risks & severity
PAPA syndrome generally presents in early childhood, with joint inflammation often being the first symptom to appear. The condition can persist throughout an individual's life, though the frequency and severity of inflammatory episodes can fluctuate [PMID:33674684]. While some individuals may experience relatively mild symptoms, others can have significant pain, joint damage, and extensive skin lesions, leading to a considerable impact on quality of life.
There is a spectrum of severity, with some individuals primarily experiencing joint issues, others mainly skin problems, and some a combination of both. The long-term risks include potential for permanent joint damage if arthritis episodes are frequent and severe, and significant scarring from pyoderma gangrenosum and cystic acne. Early diagnosis and appropriate management are important to help mitigate these potential long-term complications.
Genetic causes
PAPA syndrome is caused by pathogenic variants (sometimes called mutations) in the PSTPIP1 gene. This gene provides instructions for making a protein called proline-serine-threonine phosphatase interacting protein 1. The PSTPIP1 protein plays a role in regulating inflammation by interacting with other proteins involved in immune responses.
Specifically, the PSTPIP1 protein helps to control the activation of inflammasomes, which are multi-protein complexes that trigger the body's inflammatory response. Pathogenic variants in PSTPIP1 lead to a change in the protein's function, causing it to become overactive. This overactivity results in uncontrolled activation of the inflammasome, leading to the excessive and persistent inflammation seen in PAPA syndrome [PMID:11910214].
- PSTPIP1 proline-serine-threonine phosphatase interacting protein 1
Inheritance pattern
PAPA syndrome is inherited in an autosomal dominant pattern. This means that a person only needs one copy of the altered PSTPIP1 gene to develop the condition. If a parent has PAPA syndrome, there is a 50% chance with each pregnancy that their child will inherit the pathogenic variant and therefore also develop the syndrome.
In some cases, the pathogenic variant may arise spontaneously in the affected individual, meaning neither parent carries the altered gene. This is known as a de novo variant. Relatives of an individual with an autosomal dominant condition like PAPA syndrome may be offered genetic counselling to understand their own risks and options for genetic testing.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
A diagnosis of PAPA syndrome is typically suspected based on the characteristic clinical features: recurrent sterile arthritis, pyoderma gangrenosum, and severe cystic acne. However, not all individuals will exhibit all three symptoms, which can make diagnosis challenging. Healthcare professionals will often consider other autoinflammatory conditions that share similar symptoms.
Confirmation of PAPA syndrome is made through genetic testing to identify a pathogenic variant in the PSTPIP1 gene. In the UK, genetic testing for PAPA syndrome may be accessed via the NHS Genomic Medicine Service (GMS) pathways. A clinical genetics service or a specialist paediatric or adult rheumatology service can refer individuals for such testing, which is covered under specific R-codes for rare inherited disorders. Genetic counselling is generally offered alongside testing to discuss the implications of a diagnosis for the individual and their family.
Management & lifestyle
Management of PAPA syndrome focuses on controlling inflammatory episodes and preventing long-term complications, such as joint damage and scarring. Treatment approaches are individualised based on the specific symptoms and their severity. Non-steroidal anti-inflammatory drugs (NSAIDs) may be used for mild joint pain, but often stronger medications are required.
Immunosuppressive medications, such as corticosteroids, are frequently used to manage acute flares of arthritis and skin lesions. Biologic therapies, which target specific components of the immune system, have shown promise in managing severe cases, particularly those with significant joint or skin involvement [PMID:19166668]. Regular monitoring by a multidisciplinary team, including rheumatologists, dermatologists, and genetic specialists, is crucial. Physical therapy can also be beneficial for maintaining joint function, and skin care specialists can help manage acne and pyoderma gangrenosum.
UK care pathway
In the UK, individuals suspected of having PAPA syndrome can access care through the NHS Genomic Medicine Service (GMS). This typically begins with a referral from a GP or specialist to a clinical genetics service or a specialist centre with expertise in autoinflammatory conditions. Genetic testing for PAPA syndrome (PSTPIP1 gene) is available through the GMS, falling under relevant R-codes for rare inherited disorders as part of diagnostic testing. Genetic counsellors play a vital role in explaining the condition, inheritance patterns, and the implications of genetic testing results for patients and their families, ensuring informed decision-making.
Frequently asked questions
Is PAPA syndrome contagious?
No, PAPA syndrome is a genetic condition, not an infection. It cannot be passed from person to person through contact or any other means. It arises from changes in a specific gene.
How common is PAPA syndrome?
PAPA syndrome is considered a rare condition. The exact number of people affected is not precisely known, but it is one of the less common autoinflammatory disorders.
Can PAPA syndrome be cured?
Currently, there is no cure for PAPA syndrome. However, treatments are available to manage the symptoms, reduce the frequency and severity of inflammatory episodes, and prevent complications like joint damage and scarring. Management often involves medications that target the immune system.
Will my children inherit PAPA syndrome if I have it?
PAPA syndrome is inherited in an autosomal dominant pattern. This means if you have the condition, each of your children has a 50% chance of inheriting the altered gene and therefore developing the syndrome. Genetic counselling can provide more personalised information and support.
What kind of doctors treat PAPA syndrome?
Individuals with PAPA syndrome are typically managed by a team of specialists. This often includes a rheumatologist for joint issues, a dermatologist for skin problems, and a clinical geneticist or immunologist who specialises in genetic and autoinflammatory conditions.
References
- Sá DC, Festa C Neto. Inflammasomes and dermatology. Anais brasileiros de dermatologia. 2016. PMID: 27828627
- Koryllou A, Mejbri M, Theodoropoulou K. Chronic Nonbacterial Osteomyelitis in Children. Children (Basel, Switzerland). 2021. PMID: 34202154
- Marzano AV, Damiani G, Genovese G. A dermatologic perspective on autoinflammatory diseases. Clinical and experimental rheumatology. 2018. PMID: 29742056
- Naik HB, Cowen EW. Autoinflammatory pustular neutrophilic diseases. Dermatologic clinics. 2013. PMID: 23827244