The 82 reported cases of Blau syndrome in the 6-year-old international registry are likely far from the entire catalog of affected children.
To be included in the registry, cases must involve the mutations in the nucleotide oligomerization domain 2 (NOD2) gene, a gene that is also involved in Crohn’s disease, according to Dr. Carlos Rosé, who maintains the registry along with his colleagues Tammy Martin, Ph.D., of the Casey Eye Institute at Oregon Health and Science University, Portland, and Dr. Carine Wouters of the Catholic University of Leuven (Belgium). An additional 100-plus patients have symptoms related to those seen in Blau patients, but do not have the NOD2 mutation.
Most clinicians "have never seen a case of Blau syndrome, or think they haven’t," said immunologist Dr. Martin, who with Dr. Rosé documented that Blau syndrome could occur sporadically through a germline mutation (J. Rheumatol. 2005;32:373-5).
Long believed to be strictly familial, Blau syndrome has been found to emerge sporadically from de novo mutations as well; such cases have sometimes been classified as early-onset sarcoidosis.
Blau – whether familial or sporadic – is by all measures rare. Dr. Martin said that she has introduced Blau families to one another, helping them share information, because "chances are that wherever they live, no one in their local community has Blau." Even Wikipedia’s Blau syndrome entry is classified as a "stub" awaiting further elaboration. Epidemiologic data on Blau are scarce, and are limited mostly to Denmark, although the disease occurs all around the world.
But new information on Blau is emerging rapidly, thanks in large part to the international registry. At the 18th European Pediatric Rheumatology Congress this fall in Bruges, Belgium, Dr. Rosé of the Alfred I. duPont Hospital for Children in Wilmington, Del. updated physicians on the newly expanded phenotype for Blau, which he published, along with Dr. Martin and Dr. Wouters in September (Curr. Opin. Rheumatol. 2011;23:411-8).
The international registry, established in 2005, has revealed that a substantial minority – up to one-third – of pediatric Blau patients also have systemic disease, which can include vasculitis; renal, hepatic, or lung involvement; and severe hypertension.
Clinical presentations in the registry vary broadly, from a girl in India with cardiomyopathy and aortoarteritis to a boy in Argentina with severe renal involvement. Fever is also now seen as a characteristic of Blau flare-ups. Little of this was known 6 years ago, according to Dr. Rosé.
But the registry also points to some consistencies, which should be heartening to pediatric rheumatologists who are presented with a possible Blau case. The triad of skin, joint, and eye involvement that was first described by pediatric nephrologist Edward Blau is still considered valid, although "it is a triad over time," which makes it less diagnostically helpful, Dr. Rosé said. For example, an ichthyosis-like rash in infancy may be a consistent feature of Blau, but it is also transient, and without a biopsy it will resemble common childhood rashes.
Rather, "bogginess of joints, familial history of the same phenotype, eye disease, and negative antinuclear antibodies [ANA] are the four bullets that should raise suspicion," Dr. Rosé said, noting that eye disease in juvenile idiopathic arthritis (JIA) is usually accompanied by positive ANA.
An unexplained fever – one that is "not periodic or hectic, [like those] you see in the autoinflammatory diseases" – should also be considered in the context of possible Blau, according to Dr. Rosé.
Dr. Rosé, who currently treats children in two unrelated families with Blau, has found that the inflammatory symptoms can be managed with infliximab, which is a TNF (tumor necrosis factor) inhibitor, and that other symptoms such as hypertension can generally be controlled with appropriate drugs. Infliximab is the most commonly used medication worldwide for Blau, he said.
Thalidomide, which targets a different signaling pathway than does a TNF inhibitor, was recently used by a Japanese team to treat Blau patients successfully (Arthritis Rheum. 2010;62:250-7). Dr. Rosé said he would be hesitant to try it, however, and didn’t know of clinicians outside Japan who had. "We’re a little nervous using thalidomide in children," he said.
Of all the Blau symptoms, uveitis is "by far the most problematic" to manage, said Dr. Rosé, who estimates that 60% of Blau patients will end up with eye disease.
Dr. Martin explained that the uveitis that occurs in Blau (compared with that in JIA and other rheumatic disorders) is typically "more severe, bilateral, and generally it involves the back of the eye," in addition to the front. Unlike JIA, the uveitis in Blau will not resolve spontaneously, which is why frequent monitoring is essential. And because it involves a different part of the eye, it cannot easily be treated with steroid drops.