After sequencing, we identified a paternal splicing donor site variant c.2327+1G>C and a maternal frameshift variant c.1691_1694delGAGA (Arg564Lysfs*3) in LPIN2 (NM_014646.2, Fig. 1). c.2327+1G>C has not been reported in dbSNP, 1000 genome, ESP, ExAC, or gnomAD databases, indicating it is very rare in normal populations. This variant was predicted to disarrange the donor site according to Human Splicing Finder (www.umd.be/HSF3/HSF.shtml) and caused exon 17 deletion or intron 17 insertion either entirely or partly. This variant was first reported in an Arabic family. The proband was a 3-year-old girl with Majeed syndrome [2]. The author predicted this variant could produce an R776S change followed by 65 amino acids prior to encountering a stop codon in intron 17. c.1691_1694delGAGA, located in exon 12, led to premature termination codon at position 3 amino acids after mutation. It is expected to produce a truncated protein or lead to early degradation of mRNA through the mechanism of nonsense-mediated decay. This variant has not been reported in dbSNP, ESP, or 1000 genome databases. The frequency in ExAC database was 0.000008236, suggesting that the frequency was extremely low. Both variants were classified as pathogenic variants according to ACMG/AMP guidelines.
Majeed syndrome is a rare autosomal recessive disorder characterized by chronic recurrent multifocal osteomyelitis (CRMO). This is an early-onset disorder with a lifelong course and congenital dyserythropoietic anemia (CDA) that presents as hypochromic, microcytic anemia during the first year of life and ranges from mild to severe enough to render the patient transfusion dependent. Some individuals also develop a transient inflammatory dermatosis, often manifesting as Sweet syndrome (neutrophilic skin infiltration). It is often accompanied by recurrent fever. The diagnosis is based on clinical findings and molecular genetic testing of LPIN2, the only gene in which pathogenic variants are known to cause Majeed syndrome. Only a few cases with LPIN2 mutation have been reported, mainly in the Middle East with homozygous variants2–9.
LPIN2 encodes a phosphatidate phosphatase that plays important roles in controlling the metabolism of fatty acids at different levels. The function of LPIN2 is not well known. According to a previous study, it acts as a magnesium-dependent phosphatase, converting phosphatidic acid to diacylglycerol in the biosynthesis of triglycerides, phosphatidylcholine, and phosphatidylethanolamine. It can also act as a nuclear transcriptional coactivator of PPARGC1A and so regulate lipid metabolism10,11. Homozygous knock out Lpin2 mice displayed increases in mean platelet volume, red blood cell distribution, and lymph nodes and decreases in mean corpuscular hemoglobin, bone mineral density, and overall bone mass. They also had abnormal circulating phosphate level, hydrometra, and preweaning lethality with incomplete penetrance. LPIN2 has 19 exons and 3 lipin domains located in N-terminal (amino acid: 1-108), middle (amino acid: 469-561), and C-terminal (amino acid: 677-831), respectively (Fig. 2). Lipin domains are highly conserved in lipin proteins and lipin homologues from Saccharomyces cerevisiae (Smp2, PAH1) and Schizosaccharomyces pombe (Ned1) and the function of these domains was still unclear. Mutations on lipin domains in mice lead to fatty liver dystrophy.
We here report the first case of Majeed syndrome in the individual of Chinese heritage and with variable severity. Our patient exhibited a mild clinical phenotype, unlike in previously reported cases (Table 1). He had recurrent fever and mild to moderate hypochromic and microcytic anemia without severe CRMO. He had no physical pain, swelling, or movement disorders. Majeed reported a Palestinian Arab boy who presented at the age of 2 months with recurrent episodes of high fever and irritability12. At the age of 9 months, these episodes began to be associated with periarticular swellings with heat, tenderness, and limitation of movement. Therefore, the patient’s signs and symptoms need to be observed continuously. Our patient had severe neutropenia from the age of 6 months, and his absolute neutrophil count was 380–400/mm3. This phenotype has been reported in few cases. Mosawi reported an Arabic female with Majeed syndrome who had mild neutropenia (1080/mm3) in the neonatal period3. RAO reported a 15-year-old boy with Majeed syndrome complicated by mild neutropenia5. Those cases suggest that neutropenia may be part of the phenotype. More cases must be studied to confirm this phenotype. Treatment with IL-1 blockade was reported in Majeed syndrome13. Our patient did not use IL-1 blockade because of his age and the mildness of his phenotype.