The aim of this study was to describe the cutaneous manifestations of patients with autoinflammatory bone diseases and to evaluate the relationship between cutaneous manifestations, bone involvement, and systemic inflammation in Turkish children. This retrospective multicenter study was conducted in nine pediatric rheumatology centers between the years 2013 and 2023 in patients with a diagnosis of autoinflammatory bone disease with cutaneous manifestations. Demographic data, laboratory findings, cutaneous manifestations, bone involvement, and treatments were recorded. Two hundred and sixty-nine autoinflammatory bone disease patients were evaluated. Fifty-one patients with cutaneous manifestations (46 CRMO and five Majeed syndrome) were included in this study. The mean diagnostic delay was 16.1 ± 11.7 months in those with cutaneous manifestations and 25.3 ± 9.9 months in those with bone involvement (p = 0.02). The most common skin lesions were acne (n = 26), pustules (n = 23), and papules (n = 10). Patients with acne had more frequent male sex and higher ESR and CRP levels (p = 0.01, p = 0.03, and p = 0.04, respectively). Patients with pustules had a younger age at symptom onset and age at diagnosis and higher ESR and CRP levels (p = 0.04, p = 0.04, p = 0.04, p = 0.02, p = 0.03, respectively). In patients with CRMO, the mean time to remission was 2.1 ± 0.7 years for cutaneous manifestation and 2.9 ± 1.4 years for bone involvement (p = 0.04). Skin lesions may appear before bone lesions in autoinflammatory bone diseases, serving as an important early warning sign for diagnosis. Lesions such as acne and pustules are more common in these conditions and may contribute to the severity of inflammation in autoinflammatory bone diseases. Key Points • Skin lesions, most commonly acne and pustules, are frequently observed in autoinflammatory bone diseases. • It would be appropriate to closely monitor skin involvement to manage the disease and inflammation.

Majeed syndrome is a rare autosomal recessive autoinflammatory disorder caused by LPIN2 mutations. It is characterized by chronic recurrent multifocal osteomyelitis (CRMO), congenital dyserythropoietic anemia (CDA), and, in some cases, neutrophilic dermatoses. Its rarity and overlap with juvenile idiopathic arthritis (JIA) often lead to delayed or incorrect diagnoses. We report a 3-year-10-month-old girl with recurrent swelling and pain of the knees and ankles, associated with low-grade fever and elevated inflammatory markers for over two years. Initially diagnosed and treated as JIA with NSAIDs, methotrexate, and adalimumab, she experienced only partial improvement. MRI revealed multifocal bone marrow edema consistent with CRMO, and laboratory results demonstrated mild microcytic anemia. These findings raised suspicion of a monogenic autoinflammatory disease. Whole-exome sequencing identified two novel LPIN2 variants: c.2349del (p.Glu784ArgfsTer8), inherited maternally, and c.2327+3A>G, inherited paternally. RNA analysis confirmed exon 17 skipping, carried out quantitative RT-PCR analysis of LPIN2 mRNA,establishing pathogenicity of the splice-site variant. Together with the clinical features, these findings confirmed the diagnosis of Majeed syndrome. A review of 35 previously reported patients demonstrated that most presented before age three with CRMO and recurrent fever, but the severity of CDA varied widely. IL-1 blockade remains the most effective treatment, with sustained remission reported in multiple cases. This case expands the mutational spectrum of LPIN2 and emphasizes the importance of early genetic testing in children with recurrent osteomyelitis and anemia refractory to standard therapy. Prompt recognition enables accurate diagnosis and timely initiation of IL-1-targeted therapy, which can markedly improve outcomes.

Lipin/Pah phosphatidic acid phosphatases (PAPs) are Mg2+-dependent enzymes that catalyze the dephosphorylation of phosphatidic acid (PA) to produce diacylglycerol. Deficiency of lipin PAP activity in humans results in inflammatory disorders such as rhabdomyolysis and Majeed syndrome. Previously, we reported the first PAP enzyme structures of Tetrahymena thermophila Pah2 at 3.0 Å resolution. Here, we present five new higher resolution (1.95-2.40 Å) structures of Tetrahymena thermophila Pah2 that represent active states of catalysis, including the product analog tungstate bound to the active site, and an inactive state with a distorted active site. The structures, in conjunction with flexible docking simulations and biochemical analysis, connect two highly conserved aspartate and arginine residues in magnesium coordination and recognition of the substrate PA. Overall, this provides a structural basis for catalysis and defines a signature Asp-Arg motif in lipin/Pah PAPs that enables recognition of their lipid substrate PA, providing insight into how the haloacid dehalogenase domain of lipin/Pah PAPs evolved to act on a membrane embedded substrate.

Lipin/Pah phosphatidic acid phosphatases (PAPs) are Mg 2+ -dependent enzymes that catalyze the dephosphorylation of phosphatidic acid (PA) to produce diacylglycerol. Deficiency of lipin PAP activity in humans results in inflammatory disorders such as rhabdomyolysis and Majeed syndrome. Previously, we reported the first PAP enzyme structures of Tetrahymena thermophila ( Tt) Pah2 at 3.0Å resolution. Here, we present five new higher resolution (1.95-2.40Å) structures of Tt Pah2, in distinct catalytic states, which represent active states of catalysis, including a phospho-Asp transition state mimic, and an inactive state with a distorted active site. The structures, in conjunction with flexible docking simulations and biochemical analysis, connect two highly conserved aspartate and arginine residues in magnesium coordination and recognition of the substrate PA. Overall, this provides a structural basis for catalysis and defines a signature Asp-Arg motif in lipin/Pah PAPs that enables recognition of their lipid substrate PA, providing insight into how the HAD domain of lipin/Pah PAPs evolved to act on a membrane embedded substrate.

Lipids play essential roles as structural barriers in cell membranes, long-term energy storage, and as signaling molecules. One class of enzymes involved in lipid synthesis are lipins. Lipins are magnesium-dependent phosphatidic acid phosphatases that produce diacylglycerol, playing key roles in TAG synthesis, de novo phospholipid synthesis and metabolism. Here, we review recent advances on the structure, function, and regulation of lipins with a particular focus on the structural impacts of missense mutations associated with rhabdomyolysis, Majeed syndrome and neuropathies. Structural insights reveal that while some disease-associated mutations directly disrupt catalysis, many missense mutations are not near the active site, but still play a key role in PAP activity. With the resolved crystal structure of a lipin homolog Tt Pah2, AlphaFold, and AlphaMissense it has become increasingly possible to predict the pathogenicity and structural contributions of individual residues and mutations. Going forward, this structural information can be used to predict and understand new mutations as they arise.