An international collaboration of scientists, including researchers at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health, has identified a genetic mutation that causes a rare childhood disease characterized predominantly by inflammation and fat loss. The research suggests that the disorder, named chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), actually represents a spectrum of diseases that have been described in the literature under a variety of names. More importantly, since no effective treatment for this disease currently exists, the findings may have uncovered a possible target for future treatments.
The collaboration began when NIAMS rheumatologist Raphaela Goldbach-Mansky, M.D., started seeking the cause of inflammatory skin lesions, fat loss and fevers in two of her young patients. At a scientific meeting, she learned about recent publications by two other research groups — one led by dermatologists Antonio Torrelo, M.D., from the Boy Jesus Hospital, Madrid, and Amy Paller, M.D., from Northwestern University, Chicago, and the other led by Abraham Zlotogorski, M.D., from the Hadassah-Hebrew University Medical Center, Jerusalem — describing similar conditions. She immediately located the publications’ authors and emailed them that same night.
“It turned out they had found each other and were looking for a genetic cause and additional cases,” said Dr. Goldbach-Mansky. “I contacted them with a case report with pictures and they sent me theirs.”
Based on the clinical presentation and, particularly, the unusual skin lesions seen in the children, the researchers suspected that the children must have the same disease. Subsequent analyses — involving biopsies, blood tests and genetic testing — confirmed their suspicions. All but one child had at least one mutation in a gene called PSMB8, which had been recently identified in three adult patients with a disease called joint contractures, muscle atrophy and panniculitis-associated lipodystrophy (JMP).
PSMB8 is one of more than 20 components involved in making a cellular structure called a proteasome, which recycles proteins from cells that are stressed or dying.
“When the proteasome doesn’t function, there is a buildup of protein waste products in the cells — much like if your trash wasn’t picked up each week, it would accumulate in your driveway,” said Dr. Goldbach-Mansky.
The one patient without the mutation had a blood profile that was identical to the ones who did, and showed the same accumulation of waste products in the cells seen in children with the genetic mutation. Blood tests also showed high levels of an inflammatory chemical called interferon gamma-induced protein 10 (IP-10) that is stimulated by interferons. The chemical is produced in response to some infections, and the group suspects that it also may be produced in the cellular stress response.
The discovery, which is described in Arthritis & Rheumatism, unifies several different diseases into one spectrum of proteasome-associated autoinflammatory syndromes, said Dr. Goldbach-Mansky. She hopes that these findings will enable doctors to identify more children who fit into this spectrum of difficult-to-treat disorders so that they can develop a better understanding of the disorders and their treatment.
Despite the best treatments currently available — which, in most cases, consist of high doses of steroids — children with these disorders continue to lose fat and suffer metabolic changes that lead to a range of problems, including loss of muscle mass, dilated heart muscles and cardiac arrhythmias. Treatments for other inflammatory diseases have little, if any, effect on the prognoses of these diseases. The group’s findings, however, suggest new therapeutic targets.
The researchers are currently setting up a clinical protocol that targets the interferon pathway. Physicians and parents who suspect a child may fit the criteria for CANDLE should contact Dr. Goldbach-Mansky’s research group (Nicole Plass: at 301-496-2237 or firstname.lastname@example.org).
The research was funded by the NIAMS Intramural Research Program and the Authority for Research and Development of the Hebrew University of Jerusalem. Additional support was provided by the National Human Genome Research Institute (NHGRI), the National Cancer Institute (NCI), and other institutions. The researchers plan to collaborate with researchers in other institutes within NIH, including the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the NHGRI. They hope to learn more about the role of the gene mutation in CANDLE that leads to the disease symptoms, and to search for the genetic cause in those children who have only one disease gene, or no disease-causing mutation, so far.
The mission of the NIAMS, a part of the U.S. Department of Health and Human Services’ National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.
The NIDDK, a component of the NIH, conducts and supports research on diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition and obesity; and kidney, urologic and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe and disabling conditions affecting Americans. For more information about the NIDDK and its programs, see www.niddk.nih.gov.
NHGRI is one of the 27 institutes and centers at the NIH, an agency of the U.S. Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its website, www.genome.gov.
NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at www.cancer.gov or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.