Scientists are learning more about STAT3 loss-of-function, autosomal dominant hyper-IgE syndrome – a complicated name for a horrible, extremely rare genetic disease affecting fewer than 1,000 patients around the world – that has been known as “Job syndrome,” named for the suffering biblical character of that name.In 1966, Ralph Wedgwood and his colleagues in Seattle encountered two sisters with a significant, long-standing history of skin boils that, interestingly, were not associated with the signs of inflammation expected from such infections and were hence described as “cold” abscesses.The decision was made to call the disorder “Job syndrome,” recalling the boils afflicted upon the biblical character as a test that emerged from an exchange between God and Satan. “So Satan went forth from the presence of the Lord and smote Job with sore boils from the sole of his foot even unto his crown,” says the Bible.Dr. Joshua Milner, the chief of the laboratory of allergic diseases at the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health in Bethesda, Maryland, writes about the syndrome in the latest issue of the Rambam Maimonides Medical Journal, published in Haifa. The article is called “Learning from Job: A rare genetic disease and lessons of biblical proportions.”Milner notes that “Many fascinating observations have been made regarding the pathogenesis of the disease and the role STAT3 [a critical signaling molecule and transcription factor] plays in human health and disease. Additionally, quite a few phenotypic descriptions [observable traits] from the Book of Job are similar to those seen in patients with STAT3 LOF ADHIES (loss-of-function, autosomal dominant hyper- IgE syndrome), beyond just the boils. This complex multi-system genetic disorder is a challenge clinically and scientifically, but it also brings into question how we approach genetic syndromes beyond just the technical aspects of research and treatment.”Studying rare genetic syndromes can provide invaluable insight into fundamental pathways in health and disease, beyond the benefit to the rare patient affected by such disorders, he says.JOB SYNDROME has been studied since 1966 because of the complicated symptoms these patients can develop and for the insight the underlying cause provides into the human immune system, musculoskeletal and circulatory systems, he continues.“Since the initial naming, two substantial findings over the years have provided additional names. The first was that IgE, the antibody most tightly associated with allergic reactivity, is markedly elevated in these patients, prompting the name... It is noteworthy that the progression of terms from a malady of biblical dimension to a description of a remarkably abnormal clinical finding not necessarily central to the disease to the genetic root cause of the disorder mirrors in many ways how we have evolved in our understanding of such diseases in general,” Milner writes.Beyond the boils and infections which were noted initially, many of the symptoms with which the patients present can be found without too much stretching of the imagination in the text of the Book of Job, either from Job’s descriptions of his fate or in the descriptions by those who came to console him, he says. “It’s valuable to ponder ancient encounters with disease and affliction and contrast them to the modern ways that we understand, perceive and deal with genetic diseases.”The NIH researcher declares that “what brings Job the most solace is a lecture from God at the very end of the book. It is fundamentally about how humans and other living beings cannot possibly know or control all the various differences or ‘mistakes’ that are made that lead to good and bad outcomes in nature.”While the disease can be quite severe in many patients, Milner writes, “early management can, in a substantial subset of these patients, prevent many of the worst symptoms. Finally, once past their adolescent years, patients who have been able to manage their infections earlier in life tend to see a reduction in infection, and even in IgE levels.There can be patients who are ‘restored.’” Referencing the Bible, he continued: “The Lord changed the fortune of Job, when he prayed for his friends; and the Lord gave Job twice as much as he had before, as it were, but not without the scars of their ordeal, and not without future suffering or risk of disease.”Understanding the technical dimensions of genetic diseases so as to improve the physical health of affected patients is, of course, critical, and in this era such diseases will be genetically solved at an extraordinary rate. “However, care must be taken not to ignore the more fundamental questions of what it means to be born with a ‘mutation’ and to understand that the affected individual has been made the subject of a different set of trade-offs of gain and loss of function of different pathways inherent in any biological system in balance that sets them apart and leaves them wondering why. Caregivers should have that in mind when approaching such populations,” Milner concludes.