Majeed Syndrome

Alternative Names

  • Chronic Recurrent Multifocal Osteomyelitis, Congenital Dyserythropoietic Neutrophilic Dermatosis

Associated Genes

LIPIN 2
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WHO-ICD-10 version:2010

Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism

Certain disorders involving the immune mechanism

OMIM Number

609628

Mode of Inheritance

Autosomal recessive

Gene Map Locus

18p

Description

Majeed syndrome is a rare, autosomal-recessive autoinflammatory disorder. It is composed of three prominent clinical components which are a triad of chronic recurrent multifocal osteomyelitis (CRMO), congenital dyserythropoietic anemia (CDA), and an inflammatory dermatosis. The CRMO associated with this syndrome can be differentiated from isolated CRMO by an earlier age at onset (at age <2 years), more frequent episodes, shorter and less frequent remissions, and the fact that it is probably life long, leading to retarded growth and/or joint contractures. CDA usually presents during the first year of life and is characterized by peripheral and bone marrow microcytosis. It can be variable in severity ranging from a mild, unnoticeable anemia to a blood transfusion-dependent form. The inflammatory dermatosis is usually Sweet syndrome but can also be 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.

The diagnosis is based on clinical findings of the three components of Majeed syndrome. The diagnosis of CRMO is confirmed by radiological and technetium isotope bone scans. Bone marrow studies confirm the diagnosis of CDA. Peripheral blood films show hypochromia and microcytosis. Molecular genetic testing is implemented in those who meet clinical diagnostic criteria through mutational analysis of LIPN2, the only gene known to be associated with Majeed syndrome. The aim of management of Majeed syndrome is to treat the manifestations. CRMO is treated with nonsteroidal anti-inflammatory drugs (NSAIDs) that provide moderate improvement. If there is no 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. Physical therapy helps avoiding diffuse atrophy of muscles or contractures. CDA is treated with periodic monitoring with complete blood count (CBC) and red blood cell transfusion if indicated.

Molecular Genetics

Homozygous mutations in the LPIN2 on chromosome 18p are responsible for this syndrome. To date, three mutations have been identified in the LPIN2 in the three unrelated Arabic families. Each family had a unique mutation. Two of the three identified mutations produce a truncated protein, while the third mutation is a missense mutation that changes a highly evolutionary conserved amino acid. The function of the protein of this gene is not very clear; it may play a role in lipodystrophy in mice. In humans, the immunologic abnormalities in Majeed syndrome suggest that it plays a role in the regulation of the innate immune response.

Epidemiology in the Arab World

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Other Reports

Bahrain

Al-Mosawi et al. (2007) reported a consanguineous family with Majeed syndrome. The proband was an Arab female born after 36 weeks of gestation to first-cousin parents. She presented in the neonatal period with anemia, reticulocytosis, mild neutropenia, hepatosplenomegaly, and transient cholestatic jaundice. By age 10 months, she had a microcytic, hypochromic, Coombs' test-negative anemia with continued reticulocytosis and mild neutropenia. Iron therapy failed to correct her anemia. At age 15 months, she developed recurrent episodes of fever and multifocal osteomyelitis. The patient was treated empirically with a 6-week course of antibiotics for presumed osteomyelitis, but with no improvement. At age 19 months, CRMO was raised as a diagnostic possibility. A bone biopsy was suggested, but her parents refused the request. The patient was started on naproxen treatment (10 mg/kg twice daily). One month later, bone marrow aspiration was performed and demonstrated significant dyserythropoiesis, suggesting Majeed syndrome. A skeletal survey yielded normal findings. After that, she was started on prednisolone (1.4 mg/kg/day). One month later, the hepatosplenomegaly had regressed and there were no musculoskeletal abnormalities on examination. The prednisolone dosage was tapered to 0.7 mg/kg/day, and 8 months later, at age 3 years, she remains asymptomatic. Al-Mosawi et al. (2007) also carried out a molecular study by sequencing the coding region and splice sites of LPIN2 in the patient and her unaffected mother. They detected a homozygous single-basepair change in the donor splice site of exon 17 (c.2327+1G-C) in the patient; her mother was heterozygous at this site.

Jordan

Majeed (1994) reported on a Jordanian patient with an association of CRMO and tumoral calcinosis. This 14-year old girl was a known case of CRMO, as was an older paternal cousin. She had earlier presented with swellings in her lower limbs, left mandible, and right tibia, which were resolved with antibiotic treatment. She then presented with a large, painless, tender swelling over her right elbow, which restricted elbow movement. Radiographs showed lobulated calcification not affecting the bone cortices. The aspirate from the swelling was an aseptic, thick milky liquid, with granular hyaline and calcific material. The lobulated swelling was removed surgically. Hitological examination revealed large, irregular and flaky calcium deposits, surrounded by chronic inflammatory and foreign body reaction, and was diagnosed as tumoral calcinosis. Majeed (1994) regarded the co-occurrence of these two rare entities as being not due to chance alone.

Ferguson et al. (2005) identified two unrelated Jordanian families with Majeed syndrome. The first family had four affected individuals from two sibships and the second family had two affected siblings. The parents in both families are consanguineous with first cousin marriage in the second family. All six affected individuals from both families had CRMO (classic radiographs, multifocal isotope uptake on bone scan, prolonged course, and no response to i.v. antibiotic treatment) that was clinically manifested as recurrent bone and joint pain, CDA (anemia with dyserythropoiesis, hypochromia, and microcytosis evident on both blood smear and bone marrow aspirate examination), recurrent fevers (occurring every 2-4 weeks, lasting 3-4 days/episode), and growth failure. The phenotype was more severe in the second family, presenting with higher fevers, more extensive osteomyelitis, and severe transfusion dependent anemia. Cutaneous inflammation is also seen in Majeed syndrome. In the first family, Sweet syndrome was definitively diagnosed in two affected individuals, while two other affected individuals had a history of rash that was consistent with Sweet syndrome. The two affected individual from the second family did not have Sweet syndrome, but one of them had a history of cutaneous pustulosis. One obligate carrier from the first family had severe psoriasis and another obligate carrier from the same family was reported to have psoriasis as well but was not examined. One affected individual from the second family, evaluated at the age of 21 years, had contractures of upper and lower extremity joints, no sexual development, and maxillary bone hyperplasia. The other affected individual from the second family was ascertained at the age of 2.5 years and had not yet developed contractures or any skin manifestation. Ferguson et al. (2005) carried out also a molecular study to map, identify, and characterize the Majeed syndrome causal gene. 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. The four affected individuals in the first family were found to be homozygous for a 2201C-T transition in exon 17 of the LPIN2 gene, resulting in a ser734-to-leu (S734L) substitution. The mutation was not found in 2,300 unrelated (CEPH) chromosomes, but it had a frequency of 0.005 (4 heterozygotes in 734 chromosomes) in 367 unrelated, ethnically matched Jordanian controls. The two affected individuals in the second family were found to be homozygous for a 2-bp deletion (540delAT) in exon 4 of the LPIN2 gene. This frame shift changes the amino acid in position 180 from threonine to praline to be followed by a stop codon in position 181. The mutation was not found in 2,300 unrelated (CEPH) chromosomes, or in 367 unrelated, ethnically matched Jordanian controls.

Kuwait

[See: Palestine > Majeed et al., 1989]

Palestine

Majeed et al. (1989) were the first to report an association of congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis in an Arab family. Two brothers and a female cousin were found to be affected. All three children were born to consanguineous parents. The mode of inheritance of the condition was proposed to be autosomal recessive. The two affected brothers were also found to have Sweet syndrome, prompting the researchers to conclude that these two syndromes could be interrelated. Majeed et al. (2000) further elaborated on the profile of the family originally found to have been affected with chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia. The family now had four affected children that were followed up for a period of 9 to 16 years. All children showed a failure to thrive, with height and weight below the 5th percentile, delayed bone age, and significant hepatosplenomegaly. Abnormal hematological parameters in these patients included elevated ESR, hypochromia and microcytosis, low hemoglobin levels, significant dyserythropoeisis, hypercellular marrow, and erythroid hyperplasia. The patients required several blood transfusions. No chromosomal abnormalities were detected, excluding the possibility of Fanconi's anemia. The autosomal recessive nature of this condition was supported by the presence of two affected sibships within the same family, healthy parents, and the absence of the disease in all children born as a result of the remarriage of one of the fathers to an unrelated woman. Majeed et al. (2000) compared this disease to a similar one seen in mice causing tail kinks and limb abnormalities, which was localized to a single recessive gene on chromosome 18. Majeed et al. (2001) followed-up on the presence of Majeed syndrome in the same family reported by Majeed et al. (1989). Two siblings were affected in this family. The proband was a 2-year old girl, who presented with a history of recurrent joint pain and swelling since early infancy. The swellings affected the elbows, knee and wrist joints, and usually resolved spontaneously. Each episode, lasting 2-4 days and occurring once every 3-4 weeks, was accompanied with fever. She had no history of jaundice. Although mental development was normal, her height, weight and head circumference were below the 5th centile. Examination of the bone marrow revealed hypercellular marrow, and increased erythropoiesis with binucleated orthochromic normoblasts (24-26%). Her brother was 21-years old at the time of examination. He had had similar episodes of periarticular swelling and fever since infancy. By the age of 13-years, he was noticed to have flexion deformities of the wrists, elbows, ankles, and knees. At the time of examination, his height and weight were below the 5th centile. He was able to stand with difficulty, but could not walk. Other features included maxillary hyperplasia, a prominent forehead, absence of sexual development, slow speech, normal cognitive functions, and a negative Ham test. Radiological examination revealed vault thickening in the anterior plane. Results of bone marrow examinations were similar to his sister's. Both patients were found to be pale, with hemoglobin 40g/l, and both required several hospitalizations with blood transfusions. Majeed et al. (2001) reviewed these cases along with the earlier patients reported and stated that this syndrome was distinguished from sporadic cases of chronic recurrent multifocal osteomyelitis by nature of its early age of onset, aggressive course with frequent relapses, and a long duration of activity.

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