Congenital insensitivity to pain (CIP) comprises the rare heritable disorders without
peripheral neuropathy that feature inability to feel
pain. Fracturing and joint destruction are common complications, but lack detailed studies of
mineral and skeletal homeostasis and bone histology. In 2013, discovery of a heterozygous gain-of-function mutation in SCN11A encoding
voltage-gated sodium channel 1.9 (Nav1.9) established a distinctive CIP in three unrelated patients who suffered multiple painless fractures, self-inflicted mutilation, chronic
diarrhea, and
hyperhidrosis. Here, we studied a mother and two children with CIP by physical examination, biochemical testing, radiological imaging including DXA, iliac crest histology, and mutation analysis. She suffered fractures primarily of her lower extremities beginning at age two years, and had Charcot
deformity of both ankles and
joint hypermobility. Nerve conduction velocity together with electromyography were normal. Her children had recurrent major fractures beginning in early childhood,
joint hypermobility, and chronic
diarrhea. She had an excoriated external nare, and both children had
hypertrophic scars from scratching. Skin
collagen studies were normal. Radiographs revealed fractures and
deformities. However, lumbar spine and total hip BMD Z-scores, biochemical parameters of
mineral and skeletal homeostasis, and iliac crest histology of the mother (after in vivo
tetracycline labeling) were normal. Genomic
DNA from the children revealed a unique heterozygous missense mutation in exon 23 (c.3904C>T, p.Leu1302Phe) of SCN11A that is absent in SNP databases and alters an evolutionarily conserved
amino acid. This autosomal dominant CIP reflects the second gain-of-function mutation of SCN11A. Perhaps
joint hypermobility is an unreported feature. How mutation of Nav1.9 causes fracturing remains unexplained. Lack of injury awareness is typically offered as the reason, and was supported by our unremarkable biochemical, radiological, and histological findings indicating no skeletal pathobiology. However, low-
trauma fracturing in these patients suggests an uncharacterized defect in bone quality.