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About SickKids

January 23, 2018

SickKids-led team sheds more light on new autoinflammatory disease

An international research collaboration led by The Hospital for Sick Children (SickKids) has released their latest research project on a cohort with a rare autoinflammatory disease, A20 hapolinsufficiency (HA20). SickKids, along with their National Institutes of Health (NIH) collaborators in Washington, D.C., was the first to report on the mutated gene responsible for HA20 in 2016.

The latest research, A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease, is the first comprehensive clinical description of the cohort. It is published in the January 9 online edition of Annals of the Rheumatic Diseases.

Two sisters treated at SickKids over 20 years were the impetus for the research. As an infant, Kirsten Noseworthy, now 25, came under the care of Dr. Ronald Laxer, Rheumatologist, Project Director in the Research Institute at SickKids, and principal investigator of the study. Her mother Roslyn knew that something was seriously wrong with her first-born daughter. “I couldn’t touch her legs, she would be screaming in agony,” she says. “I couldn’t even change her diaper without causing her pain.”

From left: Kirsten, Roslyn, and Brittany Noseworthy. When sisters Kirsten and Brittany came into SickKids for care, it led to the discovery of a new autoinflammatory disease.
From left: Kirsten, Roslyn, and Brittany Noseworthy. When sisters Kirsten and Brittany came into SickKids for care, it led to the discovery of a new autoinflammatory disease.

A referral from a paediatrician brought Kirsten to SickKids and Laxer. A few years later, her younger sister Brittany was born; she also came under his care. Both sisters had an unusual form of inflammation with arthritis that presented like juvenile idiopathic arthritis (JIA), together with many mouth ulcers that present like the rare Behçet’s disease, which causes the inflammation of blood vessels throughout the body. They also had eye inflammation (which is seen in both JIA and Behçet’s), to the point where Brittany lost the vision in her left eye.

When Laxer learned that Roslyn had similar symptoms, his team began investigating a potential genetic component, especially as both sisters showed symptoms before the age of one. Working with colleagues at the NIH, a novel mutation in a gene that is involved in inflammation and immunity was identified in their family, and the associated disease was named HA20.

The latest research paper outlines how his team and their NIH colleagues searched through their databases and worked with other centres around the world to identify a total of seven families who had mutations in the same gene. The main symptoms displayed by the 16 patients in the study were recurrent oral, genital, and/or gastrointestinal ulcers; musculoskeletal and gastrointestinal complaints, cutaneous lesions, episodic fever and recurrent infections.

Ronald Laxer

“What we did in the current work was to pull the data from all the families together and report the clinical manifestations and outcome,” says Laxer, at right. “It’s important because it describes the clinical characteristics of the new disease and differentiates it from Behçet’s disease, which is what people would most commonly think about given this presentation. It should help clinicians and families who were looking for a diagnosis and might help dictate treatments. It should also help people who are doing research in the area by highlighting the importance of this gene in the inflammation pathway.”

The Noseworthy women found peace of mind having a name for their condition and are managing their symptoms well. They contributed to this research by making a few trips to the NIH in Washington, D.C. for blood work. “We were happy to support this research, to help other families get answers too,” says Brittany.

Read the initial article on HA20, published in Nature Genetics in January 2016, Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early onset autoinflammatory syndrome.