Case details

A non-consanguineous family from north-western part of India reported with three daughters (P1, P2 and P3) having polyarticular joint disease. The onset of symptoms in the third child (11 months) prompted the parents to seek medical help. The eldest sister was 5 years and 9 months old, while the second daughter was 3 years old at the time of presentation. The chronology of symptoms was similar in all three children. Joint symptoms started in infancy at around 9–10 months of age with involvement of knee and ankle and rapidly progressed to involve small joints and cervical spine too (figure 1A–C). Over the next 2 years, multiple joint involvement, pain, deformities and contractures resulted in limitation of normal routine activities, and the children were bed bound. There was no history suggestive of psoriasis or inflammatory bowel disease in family. On examination they were stunted, no facial dysmorphism was noted, had nail dystrophy and marked swelling and deformity of large and small joints. The investigations at the time of first evaluation are tabulated in the online supplementary table 1. Disease activity based on Juvenile Arthritis Disease Activity Score (JADAS-27) was 49.4, 46.6 and 45 in P1, P2 and P3, respectively (score range 0-57). Radiographs in all three sisters showed osteopenia and erosion of vertebrae without any platyspondyly (see online supplementary figure 1).

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Figure 1

(A) Knee joint swelling in P1. (B) Swelling in ankle joint (P2). (C) Swelling in wrist and finger joints (P3). (D) Electropherogram of three siblings and parents. P1, patient 1; P2, patient 2; P3, patient 3.

Initial clinical possibilities considered were Torg Winchester syndrome, Pseudorheumatoid chondrodysplasia and Familial inflammatory arthropathy. However, they fulfilled the International League of Associations for Rheumatology classification for polyarticular JIA.5 Non-steroidal anti-inflammatory drugs (naproxen) was initiated initially, and they reported relief of pain and improvement in restriction. Later, in view of rheumatoid factor being positive in eldest sister, a trial of oral prednisolone (1 mg/kg) followed by subcutaneous methotrexate (10 mg/m²/week) resulted in marked clinical improvement. Younger sisters were also treated on the same lines. All three have significantly improved and are currently ambulatory. Investigations at 2-year follow-up have been given in the online supplementary table 2. Disease activity based on JADAS-27 was 13, 7 and 7 in P1, P2 and P3, respectively. However, they are stunted with poor growth velocity.

Sanger sequencing analysis for MMP2 (Torg Winchester syndrome) and WISP3 (pseudorheumatoid chondrodysplasia) did not reveal any significant variant. Subsequently at 2-year follow-up, whole exome sequencing in P1 and P2 revealed a homozygous variant, c.832G>C; p.(Ala278Pro) in exon 4 of LACC1 (NM_001128303.2). The same variant was also present in homozygous state in P3 and heterozygous state in both the parents, as confirmed by Sanger Sequencing (figure 1D). This variant has not been observed in population databases like 1000 Genomes Project, ExAC Browser and our in-house data of 592 exomes in homozygous state. Multiple in silico prediction tools (SIFT,6 Mutation Taster7 and Polyphen8) are consistent in predicting that this variant is damaging to LACC1 protein function. LACC1 is involved in inflammasome activation, fatty acid oxidation and production of reactive oxygen species by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase and mitochondrial pathways.9 10 Mutation in this gene has been linked to JIA, inflammatory bowel disease and Behcet’s disease.4 11 12

JIA is mostly sporadic and familial aggregation is uncommon. However, there have been few reported cases worldwide where familial patients of JIA were associated with variants in LACC1. These reports have been summarised in table 1.3 4 13 14

In our patients, all three sisters had polyarthritis onset in infancy and had similar pattern of joint involvement without fever, rash or serositis. They had raised inflammatory parameters and responded well to immunosuppressant, though complete remission has not been attained. The variant c.832G>C; p.(Ala278Pro) is present in the multicopperoxidase domain of LACC1 which further supports its causative role.

It is interesting to note that patients with familial aggregation of JIA with LACC1 mutation have shown varied pattern of involvement sJIA, polyarticular and extended oligoarticular patterns. However, all have elevated inflammatory parameters, thrombocytosis and response to immunosuppressants. The role of LACC1 protein in inflammasome formation could explain its association in various inflammatory disorders. However, the exact pathogenesis need to be studied.