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.

Suggestive Findings

LPIN2-related Majeed syndrome should be suspected in individuals with the following clinical, supportive laboratory, imaging, and family history findings.

Clinical findings

• Recurrent bone pain near the joints, often of the long bones of the lower extremities
• Joint swelling and subsequent joint contracture
• Chronic recurrent multifocal osteomyelitis that is sterile
• Neutrophilic dermatosis, which may present as painful erythematous plaques, pustules, or nodules with neutrophilic infiltrates
  Note: This finding can be transient.
• Failure to thrive
• Recurrent fever
• Hepatosplenomegaly
• Gastrointestinal issues, including recurrent abdominal pain and/or recurrent diarrhea

Supportive laboratory findings

• Elevated erythrocyte sedimentation rate (ESR), typically above 100 mm/hr, and C-reactive protein (CRP), often above 50 mg/L
• Neutropenia
• Congenital dyserythropoietic, microcytic anemia, ranging from mild to severe, that sometimes requires blood transfusion
• Bone marrow biopsy that demonstrates erythroid hyperplasia with binuclearity or multinuclearity suggestive of congenital dyserythropeitic anemia
  Note: Bone marrow biopsy is not required to make this diagnosis

Imaging findings. Radiographic evidence of chronic nonbacterial osteomyelitis

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of LPIN2-related Majeed syndrome is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in LPIN2 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic LPIN2 variants of uncertain significance (or of one known LPIN2 pathogenic variant and one LPIN2 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with periodic fevers and/or autoinflammatory findings are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Individuals with LPIN2-related Majeed syndrome typically experience multisystem inflammatory symptoms, including chronic multifocal osteomyelitis, recurrent bone pain, recurrent fever, failure to thrive, dyserythropoietic anemia, and neutrophilic dermatosis. Because more than half of affected individuals have recurrent fever as one of the first manifestations, LPIN2-related Majeed syndrome should be considered in the spectrum of periodic fever syndromes in children (see Differential Diagnosis). As more families are being described, individuals with milder features are now being recognized.

To date, 32 individuals from 19 families have been identified with a pathogenic variant in LPIN2 [Chavan et al 2021; Ferguson & El-Shanti 2021; Authors, personal observation]. The following description of the phenotypic features associated with this condition is based on these reports.

Chronic recurrent multifocal osteomyelitis (CRMO). Almost all affected individuals present with recurrent bone pain or clinical or radiologic evidence of CRMO. The symptoms usually start in the first two years of life. The bone pain is usually localized in and around major joints in the long bones, especially in the lower limbs. Clinical examination may reveal local swelling, redness, or warmth of the affected bone or joint. Biopsy performed in some affected individuals reveals sterile osteomyelitis [Ferguson & El-Shanti 2021]. Due to recurrent osteomyelitis, some individuals may develop joint contractures, which may be severe enough to affect their daily living activities [Chavan et al 2021].

Hematologic findings. Affected individuals can have microcytic hypochromic anemia and sometimes may require blood transfusion. Bone marrow cytology may show abnormalities like erythroid hyperplasia and multinuclear cells suggestive of congenital dyserythropoietic anemia. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are elevated in all affected individuals (see Suggestive Findings). Neutropenia has been reported in three individuals [Ferguson & El-Shanti 2021].

Growth issues. Affected individuals experience failure to thrive or growth delay. This could be attributed to the elevated inflammatory markers, chronic osteomyelitis, and/or chronic anemia. Therefore, growth may not be affected in early infancy but may become apparent over time. It is unclear if anti-inflammatory treatment ameliorates the growth issues, although one affected individual did show improvement in weight and height after anti-inflammatory treatment was initiated [Rao et al 2016].

Dermatosis. Even though Sweet syndrome (neutrophilic dermatosis) was described in the initial family reported with LPIN2-related Majeed syndrome, skin manifestations are not common in affected individuals and sometimes may be transient. Clinical skin findings can include painful erythematous plaques, pustules, or nodules. The skin findings can occur on any part of the body, are usually patchy, and do not tend to bleed. Some affected individuals may develop erythema nodosum, which is often localized to the shins.

Gastrointestinal issues. Some affected individuals experience recurrent abdominal pain and recurrent diarrhea. However, there is limited information on these symptoms due to the small number of diagnosed individuals.

Neurodevelopment. A few affected individuals have experienced motor delay, but this has been attributed to pain due to recurrent osteomyelitis. While one case report found inflammation affecting the central nervous system [Sun et al 2021], this has not been found in other known affected individuals. There are currently no known neurologic sequelae of this condition.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

The prevalence of LPIN2-related Majeed syndrome is unknown. To date, 32 individuals from 19 families have been reported to have molecularly proven Majeed syndrome.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with LPIN2-related Majeed syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for LPIN2-related Majeed syndrome.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended (see Table 5). With anti-inflammatory treatment, many individuals experience resolution of elevated inflammatory markers and decreased bone pain. However, there is not enough data to determine if anti-inflammatory treatment will lead to resolution of all of the features of LPIN2-related Majeed syndrome.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 6 are recommended.

Agents/Circumstances to Avoid

For affected individuals managed with biologic or immunosuppressive medications, live-attenuated vaccines should be avoided, when possible.

Evaluation 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;
• If the pathogenic variants in the family are unknown, clinical assessment (history and physical exam for signs/symptoms of systemic inflammation, full skin examination for rashes, assessment of inflammatory markers [serum C-reactive protein & erythrocyte sedimentation rate], and complete blood count with differential) can be considered.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Information regarding the safety of the use of anakinra in human pregnancy is limited; however, based on animal models, the use of such therapy during human pregnancy is not anticipated to lead to an increased risk of congenital anomalies in the fetus. There is no available data on the use of canakinumab during human pregnancy. However, to date there has not been a pattern of birth anomalies reported with anti-interleukin-1 medication classes.

The use of corticosteroids during human pregnancy has been associated with an increased risk of cleft lip with or without cleft palate in exposed fetuses. Medications should be discussed with a health care provider during pregnancy or when planning to conceive [Youngstein et al 2017].

Methotrexate is known to be harmful to the developing fetus and can lead to pregnancy loss and/or birth defects. Fetal outcome depends on the dose of methotrexate used, the duration of exposure, and the gestational age of the fetus during the exposure period. Methotrexate ideally should be discontinued prior to attempting to conceive.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

The clinical trial NCT02974595 is a natural history study of autoinflammatory diseases.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

LPIN2-related Majeed syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an LPIN2 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an LPIN2 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• 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.
• Phenotypic variability was described in a family with two affected individuals. One of the affected boys had onset of symptoms at age two years and had a severe course of illness compared to his affected first cousin, who had later onset of symptoms and a milder presentation [Rao et al 2016].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has LPIN2-related Majeed syndrome or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in LPIN2.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an LPIN2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the LPIN2 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the LPIN2 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

LPIN2 encodes phosphatidate phosphatase LPIN2, or lipin-2, which belongs to the lipin family of proteins and plays a key role in lipid metabolism. Lipin-2 is most abundantly expressed in the liver, small intestine, macrophages, and the central nervous system. Lipin-2 has phosphatidic acid phosphohydrolase (PAP) activity, which catalyzes the conversion of phosphatidic acid to diacylglycerol during the synthesis of triglyceride, phosphatidylcholine, and phosphatidylethanolamine. It is also involved in fatty acid metabolism and regulation of different cellular processes, including autophagy and inflammation. Lipin-2 has been shown to regulate the activity of the large multiprotein complexes known as inflammasomes, specifically NRLP3, a key component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines [Lordén et al 2017]. Lipin-2 negatively regulates the mitogen-activated protein kinases (MAPKs) and decreases the levels of pro-interleukin-1 beta. Lipin-2 also provides a lipid environment for regulating the activity of the purigenic receptor P2X7 and prevents its overactivation, thus preventing inflammation. Lipin-2 has been shown to modulate bone homeostasis independent of the inflammasome pathway by accelerating osteoclastogenesis [Bhuyan et al 2021]. Pathogenic variants in LPIN2 cause a reduction of PAP activity, which leads to decreased lipid levels and activation of the P2X7 receptor, which in turn stimulates the NLRP3 inflammasome by potassium efflux [Lordén et al 2017].

Mechanism of disease causation. Loss of function

Author Notes

Dr Dhanya Narayanan is a DBT Wellcome Trust India Alliance Early Career clinical and Public Health research fellow. For more information on the project, visit www.saidindia.com.

Acknowledgments

We thank the DBT Wellcome Trust India Alliance for funding the study "Understanding Autoinflammatory Diseases through Clinical, Genomic and Functional Approaches" [IA/CPHE/20/1/505226].

Revision History

• 2 March 2023 (ma) Review posted live
• 6 September 2022 (dln) Original submission

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