Majeed et al. (1989) reported 2 brothers and a female cousin who had chronic recurrent multifocal osteomyelitis (CRMO; 259680) and congenital dyserythropoietic anemia (CDA); the brothers also had neutrophilic dermatosis or Sweet syndrome (608068). The clinical course of ... Majeed et al. (1989) reported 2 brothers and a female cousin who had chronic recurrent multifocal osteomyelitis (CRMO; 259680) and congenital dyserythropoietic anemia (CDA); the brothers also had neutrophilic dermatosis or Sweet syndrome (608068). The clinical course of all 3 children was similar; the unaffected parents in both families were consanguineous. Majeed et al. (2000) reported a fourth child with CRMO and CDA born into the consanguineous Arab family previously reported by Majeed et al. (1989), a brother of the female cousin. Over a period of 9 to 16 years of follow-up, the course of CRMO in these patients was characterized by early onset and 1 to 3 episodes per month, sometimes associated with mild fever. The 4 children failed to thrive; height and weight were below the 5th percentile with delayed bone age. All had significant hepatosplenomegaly and had required blood transfusions on several occasions. Their peripheral blood smears showed hypochromia and microcytosis, in contrast to the normo- and macrocytosis reported in other variants of CDA (see 224120). Majeed et al. (2000) concluded that the combination of CRMO characterized by early onset, aggressive course, and long duration with a new microcytic type of CDA represented a new autosomal recessive syndrome. Majeed et al. (2001) reported a brother and sister, born into a consanguineous Arab family, who developed Majeed syndrome at 3 weeks and 2 months of age, respectively. The diagnosis of CRMO was confirmed by radiography and technetium isotope bone scans; bone marrow studies confirmed the diagnosis of CDA, which was hypochromic and microcytic on peripheral blood smears. At age 21, the brother still had active CRMO with frequent relapses; both patients' height and weight were below the 5th percentile. The first-cousin parents and 3 other sibs were unaffected. Ferguson et al. (2005) noted that although Sweet syndrome was definitively diagnosed in only the 2 brothers reported by Majeed et al. (1989), the 2 cousins reported by Majeed et al. (1989, 2000) in that family had a history of rash that was consistent with Sweet syndrome. Ferguson et al. (2005) stated that the 2 affected sibs from the second family reported by Majeed et al. (2001) did not have Sweet syndrome, but 1 of them had a history of cutaneous pustulosis, and an obligate carrier from that family had severe psoriasis.
In 2 consanguineous Arab families with Majeed syndrome, previously reported by Majeed et al. (1989, 2000, 2001), Ferguson et al. (2005) identified homozygosity for a missense mutation (S734L; 605519.0001) and a 2-bp deletion (605519.0002) in the LPIN2 gene, ... In 2 consanguineous Arab families with Majeed syndrome, previously reported by Majeed et al. (1989, 2000, 2001), Ferguson et al. (2005) identified homozygosity for a missense mutation (S734L; 605519.0001) and a 2-bp deletion (605519.0002) in the LPIN2 gene, respectively.
The diagnosis of Majeed syndrome is based on the following findings [El-Shanti & Ferguson 2007, Ferguson & El-Shanti 2007]: ...
DiagnosisClinical DiagnosisThe diagnosis of Majeed syndrome is based on the following findings [El-Shanti & Ferguson 2007, Ferguson & El-Shanti 2007]: Chronic recurrent multifocal osteomyelitis (CRMO) that is of early onset with a lifelong course Skeletal radiographs show irregular osteolytic (radiolucent) lesions with surrounding sclerosis, usually in the metaphyses of long bones. Hyperostosis may be present in clavicular lesions. Tc-99 or Ga-67 skeletal scan shows increased uptake at the inflammatory lesions; silent (asymptomatic) lesions may be identified. MRI may be required to confirm the diagnosis, follow up lesions, or guide biopsy of an active bone lesion. Active bone lesions show increased signal intensity on T2-weighted and STIR images and decreased signal intensity on T1-weighted images. MRI is the imaging modality of choice for vertebral body lesions. Biopsy of a bone lesion shows nonspecific inflammatory changes with granulocytic infiltration. Congenital dyserythropoietic anemia (CDA) Hypochromic, microcytic anemia manifests during the first year of life and ranges from mild to transfusion dependent. Bone marrow examination shows increased erythropoiesis associated with evidence of dyserythropoiesis including up to 25% of normoblasts that are binucleated and trinucleated. The Ham test is negative. Inflammatory dermatosis [Majeed et al 2000, Majeed et al 2001, Al-Mosawi et al 2007] that may be transient and is often Sweet syndrome (neutrophilic skin infiltration) Biopsy of pustular skin lesions usually shows intraepidermal collection of neutrophils. TestingLaboratory testing is nonspecific: The most consistent findings are elevated erythrocyte sedimentation rate [El-Shanti & Ferguson 2007, Ferguson & El-Shanti 2007] and anemia. The white blood cell count may or may not be elevated. Cultures from blood, bone biopsies, and pustular lesions are always negative. Molecular Genetic Testing Gene. LPIN2 is the only gene in which mutations are known to cause Majeed syndrome.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Majeed SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityLPIN2Sequence analysis / mutation scanning 2Sequence variants 3See footnote 4Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 4. The mutation detection frequency using sequence analysis in individuals with CRMO and microcytic CDA is 100%; the mutation detection frequency using mutation scanning is unknown.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband Clinical evaluation to identify the three components of Majeed syndrome (may require bone biopsy of affected osteolytic lesion, bone marrow biopsy to document dyserythropoiesis, and skin biopsy to document neutrophilic dermatosis)Sequence analysis/mutation scanning of LPIN2 in those who meet clinical diagnostic criteriaCarrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in LPIN2.
Majeed syndrome is characterized by chronic recurrent multifocal osteomyelitis (CRMO), congenital dyserythropoietic anemia (CDA), and inflammatory dermatosis. ...
Natural History Majeed syndrome is characterized by chronic recurrent multifocal osteomyelitis (CRMO), congenital dyserythropoietic anemia (CDA), and inflammatory dermatosis. Onset of CRMO ranges from age three weeks to no later than age two years. It is characterized by short remissions, one to three exacerbations per month with each remaining for a few days, and a prolonged, probably lifelong, course. Each exacerbation consists of high fever, severe pain, and the appearance of periarticular tender soft tissue swelling, mainly involving large joints and occasionally small joints. The CRMO in Majeed syndrome is often associated with delayed bone age, growth failure, and development of permanent flexion contractures.CDA usually presents during the first year of life and varies in severity from mild to transfusion dependent. The inflammatory dermatosis is not a consistent phenotypic component of Majeed syndrome, although this may be a result of its transient nature. Of the affected individuals reported to date, two brothers had Sweet syndrome, their father had psoriasis, and an affected member of another family had cutaneous pustulosis. Hepatomegaly, neutropenia, and transient cholestatic jaundice may occur during the neonatal period. These findings have no clinical consequences because they are transient. In rare instances, neutropenia may predispose to infections. Individuals with Majeed syndrome have linear growth retardation with short adult stature. If left untreated, the quality of life is poor as a result of recurrent pain, chronic anemia, and possible complications of contractures and disuse atrophy of the muscles.The oldest individual known to have Majeed syndrome has been lost to follow up since he was about 28 years old.
Although the number of individuals reported with Majeed syndrome is too small to study genotype-phenotype correlations, the affected individuals in the family with a frameshift mutation [Majeed et al 2001] appear to have a more severe course and complications than families with other classes of mutations. Conversely, another affected individual with a splice site mutation [Al-Mosawi et al 2007] and two affected Turkish brothers with a frameshift mutation [Herlin et al 2013], who were all diagnosed and treated early, had a less complicated course. It is unclear whether their milder clinical course is attributable to the earlier detection and treatment. ...
Genotype-Phenotype Correlations Although the number of individuals reported with Majeed syndrome is too small to study genotype-phenotype correlations, the affected individuals in the family with a frameshift mutation [Majeed et al 2001] appear to have a more severe course and complications than families with other classes of mutations. Conversely, another affected individual with a splice site mutation [Al-Mosawi et al 2007] and two affected Turkish brothers with a frameshift mutation [Herlin et al 2013], who were all diagnosed and treated early, had a less complicated course. It is unclear whether their milder clinical course is attributable to the earlier detection and treatment.
The clinical diagnosis of Majeed syndrome is straightforward once the complete triad is established, and can be confirmed by demonstrating any of the various mutations in LPIN2. However, suspicion should be raised in the presence of any component, especially with an early onset in infancy and early childhood, such as unexplained congenital anemia and multifocal osteomyelitis in infancy. ...
Differential DiagnosisThe clinical diagnosis of Majeed syndrome is straightforward once the complete triad is established, and can be confirmed by demonstrating any of the various mutations in LPIN2. However, suspicion should be raised in the presence of any component, especially with an early onset in infancy and early childhood, such as unexplained congenital anemia and multifocal osteomyelitis in infancy. Because of its recurrent febrile episodic course, Majeed syndrome should also be included in the differential diagnosis of the periodic fever syndromes. The combination of bone and skin involvement, in particular, is shared by a variety of disorders including the following:Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is believed to be the CRMO of adults with skin, bone, and synovial membrane inflammation. The contribution of genetics to the etiology of SAPHO syndrome is unclear. The early onset and CDA of Majeed syndrome distinguish it from SAPHO syndrome.Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is characterized by oligoarticular, corticosteroid-responsive arthritis beginning in childhood. Pyoderma gangrenosum and severe cystic acne begin in adolescence. Mutations in PSTPIP1 are causative; inheritance is autosomal dominant. In contrast, Majeed syndrome is associated with CDA and not associated with pyoderma gangrenosum or cystic acne, and inheritance is autosomal recessive. Sporadic nonsyndromic CRMO is an autoinflammatory bone disease characterized by bone pain with or without fever with an unpredictable course of exacerbation and spontaneous remissions [El-Shanti & Ferguson 2007, Ferguson & El-Shanti 2007]. It is a sporadic disease. However, some indications suggest that it is a multifactorial disease with both genetic and environmental causes, although most causes have not yet been identified. The CRMO in Majeed syndrome is distinguished from sporadic CRMO as shown in Table 2. Furthermore, CDA is not a feature of sporadic CRMO.Table 2. Comparison of Sporadic CRMO and CRMO of Majeed SyndromeView in own windowFeatureSporadic CRMOCRMO of Majeed SyndromeAge at onsetLater onset (≤55 yrs)Early onset (1-19 months)Frequency2-4/year1-4/monthDuration1-20 yearsLifelong RemissionFrequentRare and briefLong termBenign course for mostGrowth delayContracturesInfrequentCommonCRMO = chronic recurrent multifocal osteomyelitisOther disorders to consider:Chronic multifocal non-bacterial osteomyelitis in hypophosphatasia mimicking malignancy [Girschick et al 2007]Cherubism, characterized by painless bilateral, symmetric enlargement of the mandible and/or maxilla resulting from replacement of bone with multilocular cysts composed of fibrotic stromal cells and osteoclast-like cells. Onset is typically between ages two and five years. Other bones are usually not affected and the affected person is otherwise normal. The jaw lesions progress slowly until puberty when they stabilize and then regress such that by age 30 years facial abnormalities are no longer apparent. SH3BP2 is the only gene associated with cherubism. PTPN11 mutations have also been associated with a cherubism-like phenotype in a small number of patients. Inheritance is autosomal dominant.Chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome, a chronic congenital inflammatory disorder characterized by cutaneous rash, neurologic impairment, and arthropathy. CINCA is caused by heterozygous mutations in CIAS1 [Aksentijevich et al 2002] and is distinguished from Majeed syndrome by the presence of neurologic involvement, joint symptoms, and a distinctive appearance (frontal bossing, protruding eyes, and limb shortening) and the absence of CDA.Deficiency of the interleukin-1 receptor antagonist (DIRA), a chronic inflammatory disorder that begins in the neonatal period. It presents with generalized pustulosis and osteitis. If not recognized and treated appropriately, affected individuals can develop systemic inflammatory response syndrome (SIRS) which can be a fatal complication of the disease. DIRA is an autosomal recessive disorder caused by mutations in IL1RN [Aksentijevich et al 2009]. It is distinguished from Majeed syndrome by the absence of CDA and by the distinctive radiographic bone lesions. Congenital dyserythropoietic anemia (CDA). The CDAs are a heterogeneous group of diseases in which the anemia is predominantly caused by dyserythropoiesis and marked ineffective erythropoiesis [Wickramasinghe & Wood 2005]. Three major types (I, II, and III) have been identified, as well as a few minor types. CDA I is an autosomal dominant disorder (caused by mutations in CDAN1) characterized by macrocytic anemia and occasionally associated with acrodysostosis, nail hypoplasia, and scoliosis. In contrast, Majeed syndrome is autosomal recessive and associated with microcytic CDA and no bone dysplasia or deformity. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with Majeed syndrome, the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Majeed syndrome, the following evaluations are recommended:Skeletal radiographs, if not already performedCBC, if not already performedBone marrow biopsy if significant anemia is presentExamination of the skinMedical genetics consultationTreatment of ManifestationsBecause of the rarity of Majeed syndrome, treatment is empiric.CRMO is treated as follows: Nonsteroidal anti-inflammatory drugs (NSAIDs), which provide moderate improvement. If there is an inadequate response to NSAIDs, corticosteroids are useful in controlling CRMO and skin manifestations; however, their long-term use in children is limited by side effects such as growth delay and cataracts. Tumor necrosis factor inhibitors and bisphosphonates have been reported to improve sporadic CRMO; however, the two individuals with Majeed syndrome treated with TNF-alpha inhibitors did not improve [Herlin et al 2013]. To date, bisphosphonates have not been used to treat individuals with Majeed syndrome; thus, their efficacy in this disorder is unknown. The same two affected individuals reported by Herlin et al who failed to improve with TNF blockade did respond to IL-1 blockade (IL-1 receptor antagonist [anakinra] and IL-1β antibody [canakinumab]) with clinical, radiographic, and laboratory evidence of improvement [Herlin et al 2013].Physical therapy to avoid disuse atrophy of muscles or contracturesCDA is treated with periodic monitoring with complete blood count (CBC) and blood transfusion if indicated. One patient had a splenectomy, after which the anemia markedly improved. In the two affected individuals reported by Herlin et al [2013] it is unclear if the CDA completely resolved, as a repeat bone marrow biopsy was not performed.Prevention of Secondary ComplicationsPhysical therapy can help to prevent contractures.SurveillanceThe following are appropriate:Routine CBC to determine if red blood cell transfusion is necessaryRegular pediatric careAgents/Circumstances to AvoidProlonged bed rest should be avoided because it can result in joint contractures and disuse atrophy.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherThree patients were treated with colchicine for four months with no improvement.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Majeed Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDLPIN218p11.31Phosphatidate phosphatase LPIN2The registry of LPIN2 sequence variants LPIN2 homepage - Mendelian genesLPIN2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Majeed Syndrome (View All in OMIM) View in own window 605519LIPIN 2; LPIN2 609628MAJEED SYNDROMENormal allelic variants. The genomic sequence of LPIN2 is approximately 95 kb and comprises 20 exons. Exon 1 and the majority of exon 20 are non-coding (5’ and 3’ untranslated regions). The mRNA is approximately 6245 bp and encodes a protein of 896 amino acids. It is expressed in almost all tissues. Pathologic allelic variants. Three pathologic mutations have been identified: two frameshifts and one splice site change. Four pathologic mutations have been identified: two frameshift mutations resulting from a 2-bp deletion, one splice site mutation, and one missense mutation.The fourth nucleotide variant is a missense mutation that changes an evolutionarily conserved amino acid (see Table 3).Table 3. Selected LPIN2 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1)Protein Amino Acid Change (Alias 1)Reference SequencesNormalc.991G>Tp.Ala331SerNM_014646.2 NP_055461.1c.1043C>Tp.Pro348LeuPathologicc.540_541delp.Cys181Xc.2201C>Tp.Ser734Leuc.2327+1G>Cp.Arg776Serfs*66 2c.1316_1317del (1312_1313del)p.Ser439Trpfs*15 (Leu438fs+16X) 3See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. Al-Mosawi et al [2007]3. Herlin et al [2013]Normal gene product. The protein product comprises 896 amino acids and has a lipin domain and a SMP2 domain. The protein plays a role in lipid metabolism and may play a role in lipodystrophy in mice. In humans it is apparent that it plays a role in inflammation, probably in the innate immune response.Abnormal gene product. Three out of the four identified mutations produce a truncated protein. The fourth mutation is a missense mutation that changes an evolutionarily conserved amino acid.