Congenital insensitivity to pain: Fracturing without apparent skeletal pathobiology caused by an autosomal dominant, second mutation in SCN11A encoding voltage-gated sodium channel 1.9

Abstract

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.

Keywords: Charcot arthropathy; Joint hypermobility; Mineral homeostasis; Skeletal homeostasis.

Figure 1. Family Pedigree

The proposita (arrow), whose DNA was unavailable for SCN11A analysis, presumably carries the same heterozygous missense mutation in SCN11A as her two affected children. Her mother (I-2) reportedly had diminished pain sensation and hypermobility but no fractures.

Figure 2. Clinical features of the family

A) The proposita at age 10 years has impressive hypermobility. She could march her legs up to the base of her head, could touch her thumbs to her forearms, and demonstrated 90 degrees of internal and external rotation of her hips. B) The proposita at age 23 years has scarring, loss of tissue, and ulceration of her right nasal ala from years of scratching. C) Her son has a hypertrophic scar at his posterior neck from excoriations during infancy. D) – F) The proposita's son and daughter demonstrate hypermobility.

Figure 3. Son at age 9 years

A) He has Charcot joints. Deformities affect his right leg without leg-length discrepancy. B) His right knee appears profoundly swollen from significant bony growth and fluid. C) His right ankle is enlarged from bony as well as a soft tissue swelling.

Figure 4. Radiographic studies of family members

Both ankles of the proposita at age 10 years (A) and right ankle of her son at age 9.5 years (B) show marked sclerosis, flattening, fragmentation, and deformities of the talus, ankle joints, calcaneus, and mid-tarsals consist with Charcot arthropathy. There is some sclerosis and deformity of the metatarsals. The distal tibia and fibula appear normal. The daughter's knee at age 1.5 years (C) reveals a pathologic fracture with sclerosis, fragmentation, and new bone formation of the proximal tibia, but there was good healing with mild residual metaphyseal sclerosis at age 7.5 years (D)

Figure 5. Proposita's normal iliac crest biopsy

A) A low power Golder trichrome stain of iliac crest with growth plate at the top left (pale green) shows unremarkable trabecular architecture. Scale bar = 1 mm. B) Higher magnification demonstrates normal osteoclast (top) and osteoblast (bottom) morphology. Scale bar = 100 μm.

Figure 6. Mutation Analysis

A) SCN11A gene structure showing location of mutations causing CIP. B) Sanger sequencing electropherograms show the heterozygous SCN11A mutation in the two affected siblings. The mutation is absent in the proposita's half-brother. C) Control and patients' DNA and amino acid sequences showing the C to T transition corresponding to CTC (Leu) to TTC (Phe) in codon 1302. D) Evolutionary alignment of amino acid sequence in the region of exon 23 of SCN11A containing the mutation, using the alignment tool at the UCSC Genome Browser (https://genome.ucsc.edu). The boxed amino acid, leucine (L), is the affected amino acid. It is conserved throughout all species tested, indicating importance for SCN11A function. E) SCN11A protein showing homologous Domains I–IV with transmembrane segments 1–6. F) SCN11A protein structure: The transmembrane segments (S1-S6) are illustrated, especially the S6 segments which make up the walls of the Na⁺ channel, as well as the mutation (L1302F) in our CIP patients compared to the previously reported SCN11A mutation (L811P).