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J Med Genet. Jul 2005; 42(7): 551–557.
PMCID: PMC1736104

Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome)


Background: Majeed syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. The objectives of this study were to map, identify, and characterise the Majeed syndrome causal gene and to speculate on its function and role in skin and bone inflammation.

Methods: Six individuals with Majeed syndrome from two unrelated families were identified for this study. Homozygosity mapping and parametric linkage analysis were employed for the localisation of the gene responsible for Majeed syndrome. Direct sequencing was utilised for the identification of mutations within the genes contained in the region of linkage. Expression studies and in silico characterisation of the identified causal gene and its protein were carried out.

Results: The phenotype of Majeed syndrome includes inflammation of the bone and skin, recurrent fevers, and dyserythropoietic anaemia. The clinical picture of the six affected individuals is briefly reviewed. The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families. LPIN2 was found to be expressed in almost all tissues. The function of LPIN2 and its role in inflammation remains unknown.

Conclusions: We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. Understanding the aberrant immune response in this condition will shed light on the aetiology of other inflammatory disorders of multifactorial aetiology including isolated chronic recurrent multifocal osteomyelitis, Sweet syndrome, and psoriasis.

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  • Young TL, Ives E, Lynch E, Person R, Snook S, MacLaren L, Cater T, Griffin A, Fernandez B, Lee MK, et al. Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1. Hum Mol Genet. 2001 Oct 15;10(22):2509–2514. [PubMed]
  • Zucchero Theresa M, Cooper Margaret E, Maher Brion S, Daack-Hirsch Sandra, Nepomuceno Buena, Ribeiro Lucilene, Caprau Diana, Christensen Kaare, Suzuki Yasushi, Machida Junichiro, et al. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med. 2004 Aug 19;351(8):769–780. [PubMed]
  • Cohen Jonathan C, Kiss Robert S, Pertsemlidis Alexander, Marcel Yves L, McPherson Ruth, Hobbs Helen H. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science. 2004 Aug 6;305(5685):869–872. [PubMed]
  • Keipert JA, Campbell PE. Recurrent hyperostosis of the clavicles: an undiagnosed syndrome. Aust Paediatr J. 1970 Mar;6(1):97–104. [PubMed]
  • Giedion A, Holthusen W, Masel LF, Vischer D. [Subacute and chronic "symmetrical" osteomyelitis]. Ann Radiol (Paris) 1972 Mar-Apr;15(3):329–342. [PubMed]
  • Bergdahl K, Björkstén B, Gustavson KH, Lidén S, Probst F. Pustulosis palmoplantaris and its relation to chronic recurrent multifocal osteomyelitis. Dermatologica. 1979;159(1):37–45. [PubMed]
  • Job-Deslandre C, Krebs S, Kahan A. Chronic recurrent multifocal osteomyelitis: five-year outcomes in 14 pediatric cases. Joint Bone Spine. 2001 May;68(3):245–251. [PubMed]
  • Paller AS, Pachman L, Rich K, Esterly NB, Gonzalez-Crussi F. Pustulosis palmaris et plantaris: its association with chronic recurrent multifocal osteomyelitis. J Am Acad Dermatol. 1985 May;12(5 Pt 2):927–930. [PubMed]
  • Arndt JH. Sweet's syndrome and chronic recurrent multifocal osteomyelitis. Am J Dis Child. 1987 Jul;141(7):721–721. [PubMed]
  • Edwards TC, Stapleton FB, Bond MJ, Barrett FF. Sweet's syndrome with multifocal sterile osteomyelitis. Am J Dis Child. 1986 Aug;140(8):817–818. [PubMed]
  • Nurre LD, Rabalais GP, Callen JP. Neutrophilic dermatosis-associated sterile chronic multifocal osteomyelitis in pediatric patients: case report and review. Pediatr Dermatol. 1999 May-Jun;16(3):214–216. [PubMed]
  • Laxer RM, Shore AD, Manson D, King S, Silverman ED, Wilmot DM. Chronic recurrent multifocal osteomyelitis and psoriasis--a report of a new association and review of related disorders. Semin Arthritis Rheum. 1988 May;17(4):260–270. [PubMed]
  • Prose NS, Fahrner LJ, Miller CR, Layfield L. Pustular psoriasis with chronic recurrent multifocal osteomyelitis and spontaneous fractures. J Am Acad Dermatol. 1994 Aug;31(2 Pt 2):376–379. [PubMed]
  • Vittecoq O, Said LA, Michot C, Mejjad O, Thomine JM, Mitrofanoff P, Lechevallier J, Ledosseur P, Gayet A, Lauret P, et al. Evolution of chronic recurrent multifocal osteitis toward spondylarthropathy over the long term. Arthritis Rheum. 2000 Jan;43(1):109–119. [PubMed]
  • Ben Becher S, Essaddam H, Nahali N, Ben Hamadi F, Mouelhi MH, Hammou A, Hadj Romdhane L, Ben Cheikh M, Boudhina T, Dargouth M. La périostose multifocale récurrente de l'enfant. A propos d'une forme familiale. Ann Pediatr (Paris) 1991 May;38(5):345–349. [PubMed]
  • Festen JJ, Kuipers FC, Schaars AH. Multifocal recurrent periostitis responsive to colchicine. Scand J Rheumatol. 1985;14(1):8–14. [PubMed]
  • Golla Astrid, Jansson Annette, Ramser Juliane, Hellebrand Heide, Zahn Robert, Meitinger Thomas, Belohradsky Bernd H, Meindl Alfons. Chronic recurrent multifocal osteomyelitis (CRMO): evidence for a susceptibility gene located on chromosome 18q21.3-18q22. Eur J Hum Genet. 2002 Mar;10(3):217–221. [PubMed]
  • Byrd L, Grossmann M, Potter M, Shen-Ong GL. Chronic multifocal osteomyelitis, a new recessive mutation on chromosome 18 of the mouse. Genomics. 1991 Dec;11(4):794–798. [PubMed]
  • Hentunen TA, Choi SJ, Boyce BF, Dallas MR, Dallas SL, Shen-Ong GL, Roodman GD. A murine model of inflammatory bone disease. Bone. 2000 Feb;26(2):183–188. [PubMed]
  • Khoury SA, Massad D. Consanguineous marriage in Jordan. Am J Med Genet. 1992 Jul 15;43(5):769–775. [PubMed]
  • Khoury SA, Massad DF. Consanguinity, fertility, reproductive wastage, infant mortality and congenital malformations in Jordan. Saudi Med J. 2000 Feb;21(2):150–154. [PubMed]
  • al-Salem M, Rawashdeh N. Consanguinity in north Jordan: prevalence and pattern. J Biosoc Sci. 1993 Oct;25(4):553–556. [PubMed]
  • Majeed HA, Kalaawi M, Mohanty D, Teebi AS, Tunjekar MF, al-Gharbawy F, Majeed SA, al-Gazzar AH. Congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis in three related children and the association with Sweet syndrome in two siblings. J Pediatr. 1989 Nov;115(5 Pt 1):730–734. [PubMed]
  • Majeed HA, Al-Tarawna M, El-Shanti H, Kamel B, Al-Khalaileh F. The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review. Eur J Pediatr. 2001 Dec;160(12):705–710. [PubMed]
  • Majeed HA, El-Shanti H, Al-Rimawi H, Al-Masri N. On mice and men: An autosomal recessive syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia. J Pediatr. 2000 Sep;137(3):441–442. [PubMed]
  • Vermylen C, Scheiff JM, Rodhain J, Ninane J, Cornu G. A variant of the congenital dyserythropoietic anaemia type II with structural abnormalities in the granulocytic series. Eur J Pediatr. 1986 Aug;145(3):232–235. [PubMed]
  • Sakran Waheeb, Lumelsky Dmitry, Schildkraut Vered, Smolkin Vladislav, Halevy Raphael, Koren Ariel. Chronic recurrent multifocal osteomyelitis in infancy: a case report. Clin Pediatr (Phila) 2003 Oct;42(8):741–744. [PubMed]
  • Cann Howard M, de Toma Claudia, Cazes Lucien, Legrand Marie-Fernande, Morel Valerie, Piouffre Laurence, Bodmer Julia, Bodmer Walter F, Bonne-Tamir Batsheva, Cambon-Thomsen Anne, et al. A human genome diversity cell line panel. Science. 2002 Apr 12;296(5566):261–262. [PubMed]
  • Broman KW, Murray JC, Sheffield VC, White RL, Weber JL. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet. 1998 Sep;63(3):861–869. [PMC free article] [PubMed]
  • el-Shanti H, Murray JC, Semina EV, Beutow KH, Scherpbier T, al-Alami J. Assignment of gene responsible for progressive pseudorheumatoid dysplasia to chromosome 6 and examination of COL10A1 as candidate gene. Eur J Hum Genet. 1998 May-Jun;6(3):251–256. [PubMed]
  • Bassam BJ, Caetano-Anollés G, Gresshoff PM. Fast and sensitive silver staining of DNA in polyacrylamide gels. Anal Biochem. 1991 Jul;196(1):80–83. [PubMed]
  • Lathrop GM, Lalouel JM, Julier C, Ott J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am J Hum Genet. 1985 May;37(3):482–498. [PMC free article] [PubMed]
  • Sobel E, Lange K. Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet. 1996 Jun;58(6):1323–1337. [PMC free article] [PubMed]
  • Weeks DE, Sobel E, O'Connell JR, Lange K. Computer programs for multilocus haplotyping of general pedigrees. Am J Hum Genet. 1995 Jun;56(6):1506–1507. [PMC free article] [PubMed]
  • Nagase T, Seki N, Ishikawa K, Ohira M, Kawarabayasi Y, Ohara O, Tanaka A, Kotani H, Miyajima N, Nomura N. Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain. DNA Res. 1996 Oct 31;3(5):321–354. [PubMed]
  • Péterfy M, Phan J, Xu P, Reue K. Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin. Nat Genet. 2001 Jan;27(1):121–124. [PubMed]
  • Tange Yoshie, Hirata Aiko, Niwa Osami. An evolutionarily conserved fission yeast protein, Ned1, implicated in normal nuclear morphology and chromosome stability, interacts with Dis3, Pim1/RCC1 and an essential nucleoporin. J Cell Sci. 2002 Nov 15;115(Pt 22):4375–4385. [PubMed]
  • Cao Henian, Hegele Robert A. Identification of single-nucleotide polymorphisms in the human LPIN1 gene. J Hum Genet. 2002;47(7):370–372. [PubMed]
  • Asumalahti Kati, Laitinen Tarja, Lahermo Päivi, Suomela Sari, Itkonen-Vatjus Raija, Jansen Christer, Karvonen Jaakko, Karvonen Seija-Liisa, Reunala Timo, Snellman Erna, et al. Psoriasis susceptibility locus on 18p revealed by genome scan in Finnish families not associated with PSORS1. J Invest Dermatol. 2003 Oct;121(4):735–740. [PubMed]

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