An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.

BACKGROUND: Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS: We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS: We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly. CONCLUSIONS: We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)

A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome.

Progressive myoclonus epilepsy (PME) is a syndrome characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, and varying degrees of neurological decline, especially ataxia and dementia. Previously, we characterized three pedigrees of individuals with PME and ataxia, where either clinical features or linkage mapping excluded known PME loci. This report identifies a mutation in PRICKLE1 (also known as RILP for REST/NRSF interacting LIM domain protein) in all three of these pedigrees. The identified PRICKLE1 mutation blocks the PRICKLE1 and REST interaction in vitro and disrupts the normal function of PRICKLE1 in an in vivo zebrafish overexpression system. PRICKLE1 is expressed in brain regions implicated in epilepsy and ataxia in mice and humans, and, to our knowledge, is the first molecule in the noncanonical WNT signaling pathway to be directly implicated in human epilepsy.

Neutrophil dysfunction in a family with a SAPHO syndrome-like phenotype.

SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis) is an inflammatory disorder of the bone, skin, and joints. We describe a family with multiple affected members who segregate a SAPHO syndrome-like phenotype, and we report the results of neutrophil studies and candidate gene analysis. We obtained written informed consent and a family history and reviewed medical records. We collected DNA and sequenced candidate genes, and we performed functional studies on neutrophils isolated from the proband and her mother. The pedigree segregated chronic osteomyelitis and cutaneous inflammation in a pattern that suggested an autosomal-dominant disorder. No coding sequence mutations were detected in PSTPIP1, PSTPIP2, LPIN2, SH3BP2, or NCF4. Analysis of neutrophil function in the proband, including nitroblue tetrazolium tests, myeloperoxidase assays, neutrophil chemotaxis, and neutrophil chemotaxis assays, revealed no identifiable abnormalities. However, an abnormality in the luminol, but not the isoluminol, respiratory burst assays following stimulation with phorbol myristate acetate (PMA) was detected in neutrophils isolated from the affected proband. Internal oxidant production was also reduced in the proband and her mother when neutrophils were treated with fMLP with or without platelet-activating factor, PMA alone, or tumor necrosis factor alpha alone. This family segregates a disorder characterized by chronic inflammation of the skin and bone. Functional differences in neutrophils exist between affected individuals and controls. The biologic significance of this defect remains unknown. Identification of the gene defect will help identify an immunologic pathway that, when dysregulated, causes inflammation of the skin and bone.

Autoinflammatory bone disorders.

PURPOSE OF REVIEW: This review provides an update on clinical, genetic, and immunologic aspects of the autoinflammatory bone disorders. RECENT FINDINGS: Chronic noninfectious inflammation of the bone is a clinical feature of both chronic recurrent multifocal osteomyelitis and (to a lesser degree) cherubism. The genes responsible for Majeed syndrome (LPIN2), murine chronic multifocal osteomyelitis (pstpip2), and cherubism (SH3BP2 and possibly PTPN11) have been identified. Murine models of both chronic recurrent multifocal osteomyelitis and cherubism have demonstrated that the bone inflammation is mediated by hematopoietically derived cells and can occur in the absence of a functioning adaptive immune system. As the immunologic defects become better defined, the cells of the myeloid lineage are emerging as the primary players. SUMMARY: Chronic multifocal osteomyelitis and cherubism are hereditary chronic inflammatory disorders in which bone is the primary inflammatory target. Recent genetic and immunologic discoveries demonstrate involvement of the innate immune system, which places these entities in the category of autoinflammatory disorders.

Chronic recurrent multifocal osteomyelitis: a concise review and genetic update.

Chronic recurrent multifocal osteomyelitis is an autoinflammatory disorder characterized by bone pain and fever, a course of exacerbations and remissions, and a frequent association with other inflammatory conditions. Because its etiology is largely unknown, the diagnosis is still based on clinical criteria; treatment is empiric and not always successful. The diagnosis is supported by the presence of osteolytic lesions with surrounding sclerosis apparent on radiographs, and silent asymptomatic lesions frequently appear on nuclear scans. The histologic findings in bone biopsies are nonspecific, showing inflammatory changes with granulocytic infiltration. Several observations suggest the contribution of genetic factors to the etiology of chronic recurrent multifocal osteomyelitis. Indeed, mutations in LPIN2 cause a syndromic form of chronic recurrent multifocal osteomyelitis known as Majeed syndrome, while mutations in pstpip2 cause a murine form of the disorder. The roles played by LPIN2 and the human homolog of pstpip2, PSTPIP2, in the etiology of chronic recurrent multifocal osteomyelitis are uncertain but are currently being investigated. We emphasize the need to validate diagnostic clinical criteria and develop new pathogenesis-based targeted therapy.

A splice site mutation confirms the role of LPIN2 in Majeed syndrome.

Majeed syndrome is an autoinflammatory disorder consisting of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and neutrophilic dermatosis. To date, 2 unrelated families with Majeed syndrome have been reported. Mutations in LPIN2 have been found in both families. Here we report a third consanguineous family with Majeed syndrome with a novel mutation. The patient, a 3-year-old Arabic girl, had hepatosplenomegaly and anemia as a neonate. At age 15 months, she developed recurrent episodes of fever and multifocal osteomyelitis. In addition, bone marrow aspiration demonstrated significant dyserythropoiesis, suggesting Majeed syndrome. Coding sequences and splice sites of LPIN2 were sequenced in the patient and her mother. A homozygous single-basepair change was detected in the donor splice site of exon 17 (c.2327+1G>C) in the patient; her mother was heterozygous at this site. These data confirm the role of LPIN2 mutations in the etiology of Majeed syndrome.

Familial Mediterranean fever mutation frequencies and carrier rates among a mixed Arabic population.

OBJECTIVE: Familial Mediterranean Fever (FMF) is an autoinflammatory periodic disorder characterized by febrile and painful attacks due to inflammation involving the serosal membranes. The gene implicated in this disorder, MEFV, has been cloned and mutations in its coding regions have been identified. We aimed at identifying the frequency of MEFV mutations and carrier frequency in a mixed Arabic population. METHODS: We identified 29 probands from 29 unrelated sibships segregating the disorder and representing the affected individual cohort. We screened 200 anonymous deoxyribonucleic acid (DNA) samples, representing a healthy adult cohort, for the mutations found to be common in the affected individual cohort. We also, screened anonymous DNA samples from 4 Arabic countries, namely, Egypt (231), Syria (225), Iraq (176) and the Kingdom of Saudi Arabia (107) thus enlarging our healthy adult cohort. The study was carried out between 1999 and 2002 at Jordan University of Science and Technology, Irbid and the University of Jordan, Amman, Jordan. RESULTS: Out of the 58 alleles of the 29 probands, only 31 mutations were identified and M694V and V726A are the most common. The mutation E148Q was the most common among the healthy adult cohort, but was not present in affected individuals. The collective mutant allele frequency "q" was 0.101. The expected carrier rate was 18.1% (one in 5.5) while the observed carrier rate was 18.4% (one in 5.4). CONCLUSION: E148Q has reduced penetrance and thus, a proportion of the individuals genetically affected with FMF remain asymptomatic. M694I and M680I are more prevalent in the affected individuals cohort, which points to their higher penetrance. The overall carrier rate is one in 5, but the selective heterozygote advantage could not be demonstrated in this study due to the relatively small sample size.

Familial mediterranean Fever and renal disease.

Familial Mediterranean Fever (FMF) is a genetic disorder frequently diagnosed among the Arabs. It is also prevalent among Jews, Armenians and Turks. The clinical picture consists of febrile and painful attacks such as joint or chest pain that differ in quality across patients and even within the same patient. The gene responsible for FMF, MEFV, has been cloned and mutations were identified within its coding sequence. It encodes a protein that is expected to be a down regulator of inflammation. The major renal involvement in FMF is the occurrence of amyloidosis that primarily affects the kidneys causing proteinuria and ending in death from renal failure. It can be treated by dialysis and renal transplantation, but can be prevented by a daily regimen of colchicine. Other renal manifestations of FMF are discussed.

Linkage analysis of a large inbred family with congenital megaloblastic anemia.

OBJECTIVE: Megaloblastic anemia during infancy and early childhood often reflects a hereditary disorder of cobalamin's absorption, transport, or intracellular metabolism. There are 3 well defined autosomal recessive syndromes manifesting with megaloblastic anemia due to defects in cobalamin absorption or transport, namely congenital pernicious anemia, Imerslund-Grasbeck syndrome and Transcobalamin II deficiency. The genes responsible for the 3 disorders are gene intrinsic factor (GIF), MGA1 and TCN2, as well as the gene for Transcobalamin I, TCN1 are mapped or cloned, or both. METHODS: We describe the clinical picture of 7 patients from 3 sibships, belong to one large inbred family who presented with megaloblastic anemia during infancy. The mode of inheritance follows an autosomal recessive pattern and the syndrome was completely reversed by parentral vitamin B12 therapy. The ascertainment of the family was carried out in 1998 in the Princess Rhama Children's Hospital, which is affiliated with Jordan University of Science and Technology, Jordan. We performed linkage analysis in this family for genes or regions involved in the above mentioned disorders. RESULTS: The genes implicated in the etiology of the previously mentioned disorders were excluded from being responsible for the disorder in this family. CONCLUSION: The exclusion of the involvement of GIF, MGA1, TCN1 and TCN2 in this family suggests that another gene and its product, involved in cobalamin absorption or transport, remains to be identified. A genome-wide search of the gene implicated in this family may give some insight on that gene, and its function.