Haploinsufficiency of the nerve growth factor beta gene in a 1p13 deleted female child with an insensitivity to pain.

Pain insensitivity is mediated at the genetic level by the disruption of specific genes associated with neuronal development. Mammalian in vivo and in vitro studies have shown the nerve growth factor (NGF) gene to play an integral role in nerve maintenance and function. Pain insensitivity in humans can be attributed to hereditary sensory and autonomic neuropathies (HSAN) of which there are five classes (HSAN I - HSAN V). The human nerve growth factor beta gene (NGFB) located on chromosome 1p13.2 has been found to cause HSAN V within individuals homozygous for a point mutation in NGFB. Although heterozygotes can display a milder phenotype, this has only been observed in adults. We report a karyotypically normal 5-year-old female with developmental delay, mild facial dysmorphism, and unsteady gait. Pain and thermal insensitivity were noted as were recurrent mouth ulcers, facial flushing, recurrent episodes of increased body temperature and unexplained sweating, indicative of a sensory neuropathy with mild autonomic involvement. Array comparative genomic hybridization (aCGH) analysis revealed a de-novo deletion within chromosome 1p13 of the child involving the NGFB gene. Sequence analysis of the homologous NGFB gene identified no mutation, implying that sensory neuropathy was caused by haploinsufficiency of the NGFB gene.