Inflammatory Arthritis as a Possible Feature of Coffin-Siris
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A 7-year-old boy presented with a long-standing polyarthritis for more than 3 years with “boggy” synovitis affecting both knees with fixed flexion deformity, as well as wrists, elbows, and the metacarpal and interphalangeal joints of both hands.

A previous history of developmental delay, especially affecting expressive speech, microcephaly, and dysmorphisms suggested a tentative clinical diagnosis of NBS. Ophthalmology and audiology assessments had revealed mild myopia and moderate conductive hearing loss. His increasing behavioral difficulties led to a diagnosis of autism spectrum disorder. There were frequent episodes of migraines, and epilepsy was also suspected, but repeated EEG results were normal. Brain MRI revealed a dysgenic corpus callosum with dysplastic rostrum and genu and absence of the splenium. A skeletal survey was also performed and did not reveal any evidence of skeletal dysplasia.

Subsequent full workup for polyarthritis excluded uveitis. Synovial biopsy of the right knee joint revealed chronic inflammatory synovitis consistent with inflammatory arthritis, after which treatment with methotrexate (15 mg/m2 per week subcutaneously) was instituted. Methotrexate, however, did not control the polyarthritis. Thus etanercept (0.8 mg/kg per week subcutaneously) was subsequently commenced, leading to clinical remission.

Whole-exome sequencing was performed on DNA extracted from peripheral blood from the patient, parents, and his unaffected brother to try to ascertain a genetic cause for his phenotype. In particular, targeted analysis of a list of candidate genes associated with differential diagnosis of NBS was performed, as was analysis of genes known to be associated with monogenic autoinflammation. This strategy revealed the presence of a de novo heterozygous single-nucleotide substitution in the ARID1B gene resulting in a premature stop codon in all Reference Sequence database–annotated isoforms.

Specifically, in the primary transcript, predicted to be highly expressed in human brain (and other somatic tissues), it results in a nonsense mutation in exon 20. A loss-of-function mutation in ARID1B is consistent with a diagnosis of CSS. With dideoxynucleotide sequencing, the presence of this mutation was confirmed in a heterozygous state in the patient and its absence in the clinically unaffected first-degree family members.