Abstract Details

CIP is a rare disorder. Patients have no perception of pain against injurious stimuli but are otherwise normal. It is caused by loss-of-function mutations in the SCN9A gene encoding for the T voltage-gated sodium channel Nav1.7.

Case 1 was an 18 months old male with recurrent self-injurious behavior and insensitivity to pain and heat. Case 2 was a 15 years old male patient with insensitivity to pain, juvenile arthritis, and inability to gain weight. Case 3 (elder sister) had similar complaints. Parents reported insensitivity to pain decreased with time and that both siblings began to experience pain after age 10. All cases had a normal neurologic examination and electromyography (EMG) result, except they were unresponsive to pain.

Clinical exome sequencing (CES) from peripheral blood was performed for both cases. Case 1: A homozygous frameshift variant (c.2362dupG (c.2362_2363insG) (p.Asp788GlyfsTer4)) was detected in SCN9A which was predicted as pathogenic in in silico databases. Case 2: A homozygous frameshift variant (c.3143_3154delTCAGTGGTTTTGinsA (p.Ile1048LysfsTer13)) was detected in SCN9A which was predicted as likely pathogenic in in silico databases. Both variants were not reported previously. The segregation analysis was performed for both cases. Case 2 had an additional intronic SNP (rs4303728), which in one study associated this variant with severe postoperative pain.

Homozygous and compound heterozygous mutations cause CIP. Partial regain of pain is a unique situation. The variants can be hypomorphic alleles, allowing low levels of Nav1.7- channel function. The inactivating mutation may have an attenuated effect on channel function. Further studies are required to understand the effect of the variants on Nav1.7 channel function.