Pachyonychia Congenita Project: Advancing Research and Drug Development through Collaboration
Article ID: 2023-0015-IR
Details
Article ID: 2023-0015-IR
Pachyonychia Congenita Project (PC Project) is an international patient advocacy organization dedicated to patients who suffer from pachyonychia congenita (PC). This condition is a painful and debilitating skin disorder caused by a mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16,or KRT17. Through two primary programs, namely the International Pachyonychia Congenita Consortium (IPCC) and the International Pachyonychia Congenita Research Registry (IPCRR), PC Project provides comprehensive patient support and diagnostics while uniting patients, researchers, physicians, and industry partners on a global level to advance research and drug development for meaningful treatments and, ultimately, a cure for PC.
Pachyonychia Congenita Project (PC Project) is an international patient advocacy organization dedicated to patients who suffer from pachyonychia congenita (PC). PC is a rare skin disease caused by mutations in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16,or KRT17.1,2 The organization mission statement declares: PC Project is dedicated to finding effective treatments and a cure for pachyonychia congenita, a painful, debilitating skin disorder, through helping and connecting patients, empowering research, and partnering with industry (see https://www.pachyonychia.org).
PC Project achieves its mission through two pivotal and foundational programs: the International Pachyonychia Congenita Consortium (IPCC) and the International Pachyonychia Congenita Research Registry (IPCRR). These powerful initiatives unite patients, scientists, physicians, and industry partners, establishing PC Project as the global repository for PC information and facilitating patient support. Through collaborative efforts, the organization is committed to transforming PC comprehension, enhancing patient quality of life, and propelling research and drug development in the pursuit of meaningful treatments and, ultimately, a cure for PC.
The IPCC, founded in 2004, joins researchers, physicians, and industry partners dedicated to patients impacted by PC. The primary objective of the IPCC is to foster collaboration to advance research and develop translational therapeutics for PC. De-identified data from the patient registry are made available for analysis and research, and genetically diagnosed patients from the registry can be recruited for studies.
Operating as a dynamic working organization, the IPCC has a number of committees that oversee key areas. The IPCC Steering Committee holds monthly meetings to guide PC Project and oversees all other committees. One critical committee is the Genetics Team, which comprises PC experts who regularly review cases from the physician-verified patient registry, the IPCRR. Other important IPCC groups include the Research Committee, Communications Committee, and Membership Committee.
Under the direction of the IPCC leadership, PC Project organizes and sponsors the annual IPCC Symposium. The IPCC Symposium is a scientific meeting where experts from around the world are invited to share relevant material, enrich collective knowledge, and generate research ideas while strengthening the commitment to PC patients.
With collaboration and shared expertise, the IPCC stands at the forefront of efforts to advance knowledge, research, and care for individuals living with PC. The IPCC has become an indispensable force driving progress and delivering immense value to the global PC community.
The IPCRR is a free online IRB-approved registry (WCG IRB Study #1057496) that collects and stores data from patients exhibiting clinical signs of PC. Registrants complete a comprehensive questionnaire about their symptoms and disease history, and they are offered genetic testing, personalized support, and notifications about clinical trials for PC treatments. For many patients, the registry provides a correct genetic diagnosis, often after years of uncertainty about their condition. In addition, patients are connected to a compassionate global PC community that offers encouragement and assistance in navigating life with this rare and painful disease. Patients and their families are invited to participate in activities that are sponsored by PC Project, including online forums and patient support meetings. To date, the registry has garnered over 2500 registrants from more than 50 countries. More than 1500 patients have undergone genetic testing, primarily through PC Project and the registry.
Most patients join the IPCRR not because of a doctor’s referral, but because they have been living without a diagnosis and are seeking answers. Because PC is rare, patients typically see multiple doctors in their lifetime without getting a clinical diagnosis. One reason PC is hard to diagnose is because pachyonychia means “thick nails,” but not all PC mutations have 20 thickened nails. Some patients may only have one thickened toenail and may not associate it with the painful calluses on their feet. This often makes a clinical diagnosis of PC easy to miss unless a physician understands that painful plantar keratoderma, and not thickened nails, is the most common feature of PC. Because PC is similar to other rare skin conditions, especially those with painful plantar keratoderma, it can be difficult to clinically distinguish between the conditions without genetic testing (see Fig. 1).3
Plantar keratoderma of patients who joined the IPCRR with suspected PC and received diagnostic genetic testing and support through PC Project.
Gene/protein: AAGAB/Alpha and gamma adaptin binding (punctate PPK); DSG1/Desmoglein 1 (striate PPK I); KRT6A, KRT6B, KRT6C, KRT16, KRT17/Keratins 6a, 6b, 6c, 16, 17 (pachyonychia congenita); GJB6/Connexin 30 (Clouston syndrome); KRT9/Keratin 9 (epidermolytic PPK); TRPV3/Transient receptor potential vanilloid-3 (Olmsted syndrome); DSP/Desmoplakin (dilated cardiomyopathy, woolly hair, and keratoderma); RHBDF2/Rhomboid 5 homolog (tylosis with esophageal cancer). Images are from the IPCRR database and are used with permission.
Patients most often discover PC Project’s website and registry through internet searches related to their symptoms. Upon seeing photos and reading descriptions on the website that resemble their own features, patients join the diagnostic registry with hopes of correctly identifying their condition. Participation in the registry demonstrates the value to patients of knowing the name of their disease and understanding the reasons behind their skin and nail discomfort. Even without a cure, having an accurate diagnosis is profoundly important and life-changing for patients. With a confirmed diagnosis, patients become part of a supportive global PC community that offers best care practices and encouragement to navigate life with this rare and painful disease. Furthermore, as PC research advances toward drug development, the availability of genetically confirmed patients who are ready to participate in clinical trials with precision drugs becomes critical for enrolling studies and appropriately evaluating the efficacy of these therapeutics.
The IPCRR has established an accurate portrayal of PC by defining the signs of the disease and the way it impacts the lives of individuals who suffer with it. IPCC members have analyzed, published, and presented registry findings, which has dispelled myths and taught truths about what PC is and what PC is not.1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17
Prior to formation of the registry, PC was primarily thought to be merely a nail disorder. PC pain was never mentioned in the literature. As more and more patients joined the registry, plantar pain has proven to be the most striking and primary feature of PC. PC pain may be caused by infected nails and inflamed cysts, but it is the pain from the plantar keratoderma that is most common among all types of PC and makes walking difficult and sometimes impossible. PC Project and the IPCC are still learning about the various sources of plantar pain. Blisters near and under the calluses, cracks and fissures, neurovascular structures, inflammation, and infection all can cause debilitating pain. The calluses themselves are sensitive and painful to touch. Patients in the registry report that foot pain can increase at random and for no external reasons. To alleviate plantar pain, PC patients of all ages often crawl on their knees or use mobility aids such as wheelchairs or crutches. If a patient does not have plantar keratoderma by the age of 15 years, even if they have thickened nails, they most likely do not have PC (see Fig. 2).4
Photographs of children and adults with genetically confirmed PC.
PC is a lifelong condition that affects patients of all races and genders. Many individuals with PC use mobility aids or crawl to alleviate pain. Photographs are used with permission from the IPCRR.
Continued updates and addendums to the registry have resulted in increased knowledge about PC.4,5,6 Some of the particular topics include neurovascular structures in the calluses,7 the prevalence of itching,8 ear pain,9 laryngeal thickening,9,10 and possible association with hidradenitis suppurativa.11
Information and data from the registry have helped to:
PC Project has always offered diagnostic genetic testing as part of the registry, but in January 2021, the organization’s testing panel increased from 9 genes to 49 genes (AAGAB, ADAM10, AP1S1, AQP5, SLURP1, CAST, *USB1*, CTSC, DSC2, DSG1, DSP, EDA, ENPP1, *FZD6*, GJA1, GJB2, GJB3, GJB4, GJB6, GRHL2, *IVL*, JUP, KANK2, KLHL24, KRT1, KRT2, KRT5, KRT6A, KRT6B, KRT6C, KRT9, KRT10, KRT14, KRT16, KRT17, KRT83, LOR, MBTPS2, PKP1, POMP, RHBDF2, RSPO1, SASH1, SERPINB7, SNAP29, TRPV3, *TAT*, VPS33B, WNT10A). PC Project uses an accredited laboratory to conduct genetic testing. Cases from the IPCRR, including data, photos, and genetic testing results, are reviewed monthly with the IPCC Genetics Team of expert doctors and scientists to verify the findings or to determine what additional testing is necessary to validate the genetic testing results. As a result, the registry has been consistently collecting data about medical conditions similar to PC from patients who join without a diagnosis. Although most IPCRR patients have PC mutations, the registry now contains data from patients with other mutations that cause palmoplantar keratodermas (see Tables 1 and 2; https://www.pachyonychia.org/other-conditions-with-painful-ppk/). PC Project invites all those who suffer with suspected PC or any type of painful genetic palmoplantar keratoderma (PPK) to join the diagnostic registry (https://www.pachyonychia.org/patient-registry/).
| Gene | Number tested and fully enrolled in IPCRR |
|---|---|
| KRT6A | 458 |
| KRT6B | 103 |
| KRT6C | 38 |
| KRT16 | 403 |
| KRT17 | 167 |
Data collected up to August 2023 (https://www.pachyonychia.org/pc-data/).
| Gene | Number tested and fully enrolled in IPCRR |
|---|---|
| AAGAB | 11 |
| GJB6 | 36 |
| DSG1 | 22 |
| DSP | 5 |
| FZD6 | 8 |
| KRT1 | 6 |
| KRT9 | 11 |
| RHBDF2 | 4 |
| TRPV3 | 17 |
| WNT10A | 2 |
Data collected up to August 2023 (https://www.pachyonychia.org/other-conditions-with-painful-ppk/).
In addition to the foundational programs of the IPCC and the IPCRR, PC Project provides services related to raising awareness, research and drug development, and patient support.
Education and raising awarenessPC Project plays a crucial role in raising awareness about PC within the medical and scientific community and society at large. By participating in conferences, grand rounds, and organizing awareness campaigns, PC Project educates healthcare professionals, researchers, and the public about the features and challenges of PC. Increased awareness leads to earlier diagnosis, better understanding, and improved care for PC patients.
Research and drug developmentPC Project actively supports and funds research initiatives to understand the underlying causes of PC and develop effective treatments.15 Updates and addendums to the registry have resulted in increased knowledge about PC.5 By collaborating with scientists and clinicians worldwide, especially within the IPCC, PC Project facilitates the exchange of knowledge and the advancement of scientific breakthroughs. PC Project provides the patient voice in clinical studies, offering focus groups, surveys, and patient feedback to ensure a smooth trial process. With a registry of known genetically confirmed patients in a family-like community, PC Project efficiently notifies patients about opportunities to participate in trials.
Patient supportPC Project provides comprehensive support to PC patients and their families, addressing the physical, emotional, and social aspects of living with PC. Aspects of patient support provided by PC Project include the following:
PC Project is an invaluable resource that has significantly enhanced the lives of those affected by this rare genetic disorder. By empowering patients with hope, practical help, and a sense of community, PC Project helps patients successfully navigate life despite the challenges of this rare and painful disease. Through the collective components of its two primary programs, the IPCC and the IPCRR, PC Project provides comprehensive diagnostic support to patients, fosters collaboration among researchers and physicians, and assists industry partners at every stage of a clinical trial by providing the patient voice and inviting registry patients to participate. All services and programs of PC Project are designed to lead to the overarching goal of finding effective treatments and, ultimately, a cure for PC, so that patients with PC can live without pain, isolation, or embarrassment.
EOT has acted as an investigator in clinical trials for Palvella Therapeutics and Kamari Pharma; received research funding from Kamari Pharma and Unilever; provided consultancy services to Azitra Inc., Palvella Therapeutics, and Kamari Pharma; and acted as an invited speaker for Almirall. EOT has not received compensation for these activities with all funding going to the university. The remaining authors declare no conflict of interest.
