Clinical characteristics: Individuals with LPIN2-related Majeed syndrome typically experience multisystem inflammatory symptoms, including chronic sterile multifocal osteomyelitis, recurrent bone pain, recurrent fever, failure to thrive, dyserythropoietic anemia, and neutrophilic dermatosis. Recurrent bone pain is frequently localized near the joints, often of the long bones of the lower extremities. Recurrent osteomyelitis with joint swelling can lead to subsequent joint contractures. Congenital dyserythropoietic, microcytic anemia can range from mild to severe and sometimes requires blood transfusion. Neutrophilic dermatosis typically presents as transient painful erythematous plaques, pustules, or nodules with neutrophilic infiltrates. Other features of LPIN2-related Majeed syndrome include the development of hepatosplenomegaly and gastrointestinal symptoms, such as recurrent abdominal pain and/or recurrent diarrhea. As more families are being described, individuals with milder features are now being recognized.
Diagnosis/testing: The diagnosis of LPIN2-related Majeed syndrome is established in a proband with suggestive findings and biallelic pathogenic variants in LPIN2 identified by molecular genetic testing.
Management: Treatment of manifestations: Anti-inflammatory treatment decreases inflammation and reduces flare-ups. Anti-inflammatory drugs can include anti-interleukin-1 (anti-IL-1) therapy (anakinra 1.5 mg/kg/day with titration as needed or canakinumab 2 mg/kg every 4 or 8 weeks), nonsteroidal anti-inflammatory drugs, corticosteroids, or methotrexate. While one of the anti-IL-1 therapies is the drug of choice, these drugs may not be universally available. Severe anemia may require blood transfusion. Physical therapy and/or occupational therapy can help motor delays and joint contractures.
Surveillance: Measurement of inflammatory markers (ESR, CRP) and growth parameters, assessment of range of motion of joints, and physical examination to assess for hepatosplenomegaly and dermatosis at each visit. Complete blood count (CBC) with differential to assess for anemia and neutropenia every six months. Abdominal ultrasound as clinically indicated to monitor those with hepatosplenomegaly.
Agents/circumstances to avoid: For affected individuals managed with biologic or immunosuppressive medications, live-attenuated vaccines should be avoided, when possible.
Evaluations of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual to identify as early as possible those who would benefit from prompt initiation of anti-inflammatory treatment. Evaluations can include targeted molecular genetic testing (if the pathogenic variants in the family are known) or clinical assessment (history and physical exam for signs/symptoms of systemic inflammation, full skin examination for rashes, assessment of inflammatory markers [serum CRP and ESR], and CBC with differential) if the pathogenic variants in the family are not known.
Pregnancy management: There is limited data on the safety of anakinra or canakinumab during human pregnancy, although no pattern of anomalies in exposed fetuses has been reported. The use of corticosteroids during human pregnancy has been associated with an increased risk of cleft lip with or without cleft palate. Methotrexate should be avoided in pregnancy, as it is known to be harmful to the developing fetus and can lead to pregnancy loss and/or birth defects.
Genetic counseling: LPIN2-related Majeed syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an LPIN2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the LPIN2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
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