PEDIATRICS Vol. 105 No. 5 May 2000, pp. 1152-1154
The Crigler-Najjar syndrome was first described in this journal in 1952.(1) The majority of patients died with kernicterus during the neonatal period. In 1958, the use of phototherapy to treat neonatal jaundice was first reported in England.(2) This therapy was not adopted in the United States until 1968 when the first randomized controlled trial to prevent neonatal jaundice was reported, also in this journal.(3) Little attention was paid to the first reports that phototherapy could be used to modify neonatal hyperbilirubinemia in Crigler-Najjar patients.(4,5) Over the next 20 years, it became apparent that this is an effective, if inconvenient, therapy. An increasing number of Crigler-Najjar patients now survive into adolescence. The syndrome can be "cured" by hepatic transplants first conducted in 1986.(6) The enzymatic defect in the liver was identified in 1957 (7) and the locus of the missing gene in 1992. (8) Advancements have been slow but steady over the past 45 years.
Progress, up to this point, has occurred because of cooperation between patients, parents, plus a small, but varied group of basic research workers, hepatologists pediatricians, geneticists, and surgeons.
Many of the basic research workers had never seen a patient with the disease. Few doctors in practice have ever seen a patient with the disease, or have actually ever taken care of one of these patients.
The parents felt isolated, alone, and were eager to contact other parents to discuss their "special children." They had never been invited to a meeting on their "disease." The first international meting of all of these diverse groups was held in 1996. It was organized by Rockefeller University Hospital, the University of Vermont, the National Foundation, and Olympic Medical Supply Company.
The second meeting was held in June 1999, sponsored by the Rockefeller University Hospital, the University of Vermont, and the Clinic for Special Children in Strasburg, Pennsylvania. It was held in an ideal setting: Strasburg, Pennsylvania, where one of the largest groups of patients with this disease is taken care of at this clinic.
During the 3-year interval since the first meeting, some very significant progress has been made. Phototherapy remains the major treatment modality, but it remains inconvenient, and for adolescents, it is
not very effective.
Kappas and colleagues at Rockefeller University Hospital reported further progress on the use of the heme oxygenase inhibitor, Sn-mesoporphyrin (SnMP) to moderate severe hyperbilirubinemia in Crigler-Najjar type I patients. To date, 4 patients have participated in prolonged clinical research center studies of this agent in trials lasting up to 400 days. In all, pronounced (30%-50%) declines in serum bilirubin levels have been sustained for periods ranging from 3 to 7 weeks after single or multiple doses of SnMP. The inhibitor has been provided to other investigators, with similar results. These responses offer a pharmacological approach to transiently controlling the acute, severe, and dangerous episodes of hyperbilirubinemia that Crigler-Najjar type I patients may experience after various stresses. Long-term control of the heme oxygenase gene using retrovirus-anti-sense oligonucleotide methodologies have also been achieved by the Rockefeller group and may have clinical potential in this disorder.
The most exciting new therapy discussed was the recent progress in gene therapy. Kren et al (13) reported success in the Gunn rat model using gene repair. A team led by M. Blaese, MD, Kimeragen; C. Steer, University of Minnesota; J. Roy-Chowdhury, Albert Einstein College of Medicine, New York, New York; and H. Morton, MD, the Clinic for Special Children, Strasburg, Pennsylvania, announced a planned study to repair the gene using chimeroplasty in humans starting in 2000. If successful, this could be a major breakthrough and lead the way to treating other more common genetic disorders such as hemophilia.
It is difficult to organize clinical trials of therapies in a very rare disease. Now that there are several possible therapies, which need to be tested, it is important to try to gather together and inform the parents of as many patients with this rare disease as possible. There are 3 countries where patient and physician groups have been formed The Netherlands, Saudi Arabia, and the United States. It is estimated that there are >400 patients with this condition in the world. Now would seem to be an appropriate time to increase communication between these groups and research workers. Clinical trials of the possible new therapies will have to be conducted among Crigler-Najjar patients; therefore, it is important that as many physicians and patients as possible are aware of the new, rapid research progress in treating this disease so that patients can participate in trials and benefit from the new therapies To facilitate this progress, we Rockefeller University Hospital/University of Vermont) have created an Internet site, www.crigler-najjar.com, which will serve as an information source for physicians and patients. This site is in operation and currently contains information on the disorder and its management. It also contains an extensive bibliography of articles on Crigler-Najjar syndrome and has information about the next symposium on Crigler-Najjar syndrome, which was held on April 28, 2000 in The Netherlands.
Jerold F. Lucey, MD and Gautham K. Suresh, MD
Attallah Kappas, MD
Received for publication Feb 23, 2000; accepted Feb 28, 2000.
Address correspondence to Jerold F. Lucey, MD, Department of Pediatrics, University of Vermont College of Medicine, Burlington, VT 05405.
1.Crigler JF, Najjar VA Congenital familial non-haemolytic jaundice with kernicterus. Pediatrics. 1952; 10:169-180